Ianalumab

*仅供医学专业人士阅读参考 聚焦SSc治疗最新突破，解析创新疗法的临床证据与应用策略。 撰文丨kangkang 系统性硬化症（systemic sclerosis，SSc）是一种以血管病变、免疫失调及皮肤和内脏器官纤维化为核心特征的系统性自身免疫性结缔组织病，其疾病相关死亡率居自身免疫性风湿病之首。传统治疗主要依赖免疫抑制剂和对症支持，虽能部分稳定病情，但难以逆转纤维化。 近期，发表于Nature Reviews Rheumatology的综述《Emerging therapies for the treatment of systemic sclerosis》系统地概述了一系列新型药物和细胞疗法，标志着SSc治疗领域正迎来一场深刻变革。本文旨在梳理最新进展，为临床医生提供前沿的诊疗视角与决策依据。 病理核心与传统治疗 SSc的病理生理过程可概括为“三重打击”：血管病变、免疫失调和进行性纤维化。传统治疗遵循个体化原则，基础治疗强调非药物干预，如戒烟、保暖及锻炼。 针对脏器受累：皮肤病变首选甲氨蝶呤(MTX)或吗替麦考酚酯（MMF）；间质性肺病以MMF或环磷酰胺(CYC)为基础；胃肠道症状主要应用质子泵抑制剂及对症处理；血管病变如雷诺现象，主要使用钙通道阻滞剂等血管扩张剂。对于快速进展型，可评估自体造血干细胞移植（AHSCT）。这些方案主要目的在于稳定病情而非逆转病情。 新型有效疗法 过去五年间，SSc治疗取得了关键突破，三类药物（见表1）尤为突出： 1.尼达尼布（Nintedanib）：作为一种多靶点酪氨酸激酶抑制剂，其能显著减缓SSc相关间质性肺病（SSc-ILD）患者的肺功能年下降率（以FVC衡量），由此成为SSc-ILD抗纤维化治疗的支柱。 2.托珠单抗（Tocilizumab）：作为IL-6受体拮抗剂，其能改善早期弥漫性皮肤型SSc患者皮肤评分的趋势，并在后续分析中体现出对稳定肺功能的显著益处，使其成为活动性、炎症性表型患者的重要选择。 3.利妥昔单抗（Rituximab）：尽管说明书未明确，但高质量的RCT证据（如DESIRES试验）表明，这种抗CD20的B细胞耗竭剂能显著改善皮肤纤维化（mRSS），并在RECITAL试验中显示出与环磷酰胺相当的稳定肺功能效果，且安全性更优，使其在临床中的应用日益广泛。 表1：改变系统性硬化症治疗管理的临床试验（主要或次要结局阳性） 注：CTD：结缔组织病；dcSSc：弥漫性皮肤型系统性硬化症；FVC：用力肺活量；ILD：间质性肺病；K-BILD问卷：King's简要间质性肺病问卷；mRSS：改良Rodnan皮肤评分；PPF：进展性肺纤维化；RCT：随机对照试验；SSc：系统性硬化症。 临床试验中的前沿探索 随着对发病机制理解的深入，治疗策略转向针对特定病理环节的精准靶向。以下六大方向代表了当前最具前景的研发前沿（具体疗法详见表2）： 1 靶向成纤维细胞的策略 ■核心机制：直接抑制成纤维细胞的活化、增殖或诱导其静息，从效应端阻断纤维化进程。 ■临床试验疗法：ENV-101、Fipaxalparant、Ziritaxestat、RG6315。 2 双重靶向成纤维细胞与免疫细胞 ■核心机制：通过单一靶点同时调控免疫炎症和成纤维细胞活化，干预免疫-纤维化交叉对话。 ■临床试验疗法：Nerandomilast、CAN10、Dersimelagon、Asengeprast、CAL101、Itacitinib、Vixarelimab、Nemolizumab。 3 靶向B细胞与自身抗体 ■核心机制：清除B细胞/浆细胞、抑制其生存因子或加速清除致病性自身抗体，从体液免疫源头干预。 ■临床试验疗法：Efgartigimod、Belimumab、Ianalumab、Telitacicept、Inebilizumab、抗CD19 CAR-T细胞、抗BCMA CAR-T细胞、CD19xCD3/CD20xCD3/BCMAxCD3 BITEs。 4 T细胞靶向策略 ■核心机制：调控T细胞的活化、共刺激、分化及功能，纠正适应性免疫失调。 ■临床试验疗法：Amlitelimab、Tulisokibart、Brodalumab、Guselkumab。 5 其他免疫调节策略 ■核心机制：靶向固有免疫或其他非特异性免疫通路，广泛抑制炎症反应。 ■临床试验疗法：Tibulizumab、Anifrolumab、Efzofitimod。 6 兼具血管作用的抗纤维化策略 ■核心机制：主要针对血管病变，同时通过改善缺氧、抑制内皮-间质转化等机制发挥抗纤维化作用。 ■临床试验疗法：Avenciguat、Ifetroban。 表2：当前正在或即将进入临床试验的系统性硬化症疗法 注：αMSH：α-黑素细胞刺激素；BAFF：B细胞活化因子；BCMA：B细胞成熟抗原；BiTEs：双特异性T细胞衔接器；cAMP：环磷酸腺苷；CAR：嵌合抗原受体；cGMP：环磷酸鸟苷；DR3：死亡受体3；HARS：组氨酰tRNA合成酶1；IFNAR1：干扰素-α/β受体亚基1；IL-31RA：IL-31受体A；IL-1RAP：IL-1受体辅助蛋白1；ILCs：固有淋巴细胞；JAK1：Janus激酶1；LPA：溶血磷脂酸；LPAR1：溶血磷脂酸受体1；MC1R：黑皮素受体1；OSM：抑瘤素M；PDE4B：磷酸二酯酶4B；sGC：可溶性鸟苷酸环化酶；SSc：系统性硬化症；STAT：信号转导与转录激活因子；TFH细胞：滤泡辅助T细胞；TH细胞：辅助T细胞；TL1A：TNF样配体1A；TPR：血栓烷前列腺素受体；dcSSc：弥漫性皮肤型系统性硬化症；FVC：用力肺活量；ILD：间质性肺病；PPF：进展性肺纤维化。 以上创新疗法中，部分疗法因其在临床试验中展现的显著疗效潜力与疾病治疗作用，已成为SSc重点关注的方向： 1 靶向B细胞的深度免疫调控 以自体抗CD19 CAR-T细胞疗法为代表的深度B细胞耗竭策略，在难治性、进展型SSc患者中显示出突破性潜力。临床观察证实，该疗法可快速改善mRSS、稳定甚至逆转内脏纤维化进程，并显著缓解血管功能障碍。尤为重要的是，其临床获益在CAR-T细胞从外周血清除后仍能长期维持，提示其可能诱导了深度的免疫重建，为根治本病带来了希望。基于同一理念，靶向BCMA等B细胞谱系标志物的双特异性T细胞衔接器（BITEs）也正在积极探索中，旨在实现更彻底的体液免疫清除。 2 核心致病通路的精准干预 Anifrolumab（抗IFNAR1单抗）可有效抑制SSc患者的Ⅰ型干扰素信号通路，并下调纤维化相关基因表达，显示出明确的抗纤维化潜力，目前正在进行Ⅲ期验证。Efgartigimod（FcRn拮抗剂）通过阻断IgG再循环、加速其分解代谢，可显著、快速且安全地降低包括致病性自身抗体在内的总IgG水平，为从源头上干预SSc的体液免疫致病环节提供了全新机制。 3 协同干预纤维化与血管病变 可溶性鸟苷酸环化酶（sGC）激动剂Avenciguat旨在同时改善SSc的纤维化与血管病变两大核心病理环节，代表了协同治疗的新方向。其作用不依赖于内源性一氧化氮，在氧化应激环境下依然有效，尤其适用于SSc的病理生理特点。 此外，CONQUEST平台试验作为风湿病领域首个平台试验，极大提升了新药研发效率。在此框架下评估的Nerandomilast（高选择性PDE4B抑制剂）及可同时中和IL-17A与BAFF的双特异性抗体Tibulizumab，均体现了通过创新研发模式与多通路协同调控实现更高效治疗的理念。这些进展标志着SSc治疗正从传统的非特异性免疫抑制，迈向以精准靶向和深度免疫调控为特征的疾病治疗新阶段，为改善患者长期预后带来了实质性希望。 总结 随着对疾病分子机制理解的深化和临床试验结果的不断涌现，未来SSc的治疗将更加个体化、精准化，为每位SSc患者量身定制最优治疗方案将成为可能，从而优化治疗路径。临床医生深刻理解不同药物的作用机制与临床定位，是将前沿进展转化为患者长期获益的基石。 医学界风湿免疫领域交流群正式开放！ 长按识别二维码 加入我们吧！ 参考文献： [1]Distler JHW, Kuwana M, Assassi S, et al. Emerging therapies for the treatment of systemic sclerosis. Nat Rev Rheumatol. 2025 Oct;21(10):612-625. [2]邹和建,朱小霞,戴生明,等. 系统性硬化病诊疗规范[J]. 中华内科杂志,2022,61(8):874-882. 责任编辑：墨水 *"医学界"力求所发表内容专业、可靠，但不对内容的准确性做出承诺；请相关各方在采用或以此作为决策依据时另行核查。 ↓↓↓点击「阅读原文」学习更多临床技能

iStock, Artem_Egorov With immunology and inflammation blockbusters like AbbVie’s Skyrizi and Rinvoq reeling in nearly $7 billion combined in the third quarter, the pipeline-in-a-product strategy has never been more attractive. Last year, biotech executive and entrepreneur Andrew Pannu told BioSpace that immunology and inflammation could be a particularly attractive therapeutic space because of its “pipeline-in-a-product” potential. It’s a playbook many biopharma companies—including Novartis and Vertex—appear increasingly keen to operate by. In one of 2024’s biggest acquisitions—and Vertex’s largest-ever—the Boston-based pharma subsumed immunotherapy player Alpine Immune Sciences and its lead asset povetacicept for $4.9 billion. A dual antagonist of the BAFF and APRIL cytokines for autoimmune and inflammatory diseases, povetacicept is currently being studied in Phase III and Phase II/III trials for IgA nephropathy (IgAN) and primary membranous nephropathy, respectively, and Vertex said in a press release last month that it has “pipeline-in-a-product potential across a range of B cell–mediated diseases.” This is also a strategy echoed in the immunology and inflammation (I&I) space by Novartis, which recently presented Phase III data for ianalumab in Sjögren’s disease at the American College of Rheumatology Convergence congress. If approved, it would be the first targeted treatment for this common rheumatic autoimmune disease. But Novartis isn’t stopping there. Ianalumab, a B cell–depleting antibody that, like povetacicept, targets the BAFF receptor, is also in mid- to late-stage development for systemic lupus erythematosus (SLE), lupus nephritis and systemic sclerosis as well as earlier-stage development for three hematological indications. “We’ve had this common theme around saying that when we understand a drug and its mechanism of action, we will evaluate it in multiple indications simultaneously,” Shreeram Aradhye, president of development and chief medical officer at Novartis, told BioSpace last month. The company took the same approach, Aradhye said, with remibrutinib, which was approved by the FDA in September as Rhapsido, the first BTKi drug for chronic spontaneous urticaria (CSU). Elsewhere in the pipeline, the company is also studying remibrutinib in pediatric chronic spontaneous urticaria, hidradenitis suppurativa, multiple sclerosis and food allergy, among other indications. “Having an asset where we understand the mechanism of action, making sure that we garner its full value by evaluating it in multiple places where it could help in ambitious parallel programs that are being run, has also worked out well for us,” Aradhye said. Biogen, too, has spent big money to expand its presence in I&I. In May 2024, the big biotech snapped up Human Immunology Biosciences , aka HI-Bio, for up to $1.8 billion. At the center of the deal was felzartamab, whose mechanism of selectively depleting CD38+ cells could give Biogen “applicability across a range of immune-mediated diseases,” BMO Capital Markets analysts wrote in a note to investors at the time. With the global immunology market projected to exceed $257 billion by 2032, it’s no wonder so many companies are looking to optimize their shots on goal. Proof Is in the Market If I&I–focused companies need additional incentive to embark on this strategy, they need look no further than AbbVie. In the third quarter, the company’s two-headed immune blocking behemoth—made up of Skyrizi and Rinvoq—brought in nearly $7 billion combined, accounting for almost half of AbbVie’s income for the quarter. Together, the two drugs cover a host of immune-mediated diseases. Skyrizi is indicated for plaque psoriasis, psoriatic arthritis, Crohn’s disease and ulcerative colitis, while Rinvoq is approved to treat rheumatoid arthritis, atopic dermatitis and ankylosing spondylitis. Rinvoq’s reach could soon expand further, with recent successful Phase III data in alopecia areata and vitiligo . And of course, Skyrizi and Rinvoq are successors of AbbVie’s Humira—which long held the title of the world’s top-selling drug. The blockbuster held FDA approvals in upwards of 15 autoimmune and inflammatory diseases since its initial greenlight for rheumatoid arthritis in 2002 . In an interview with BioSpace , Graig Suvannavejh, managing director of Equity Research at Mizuho Securities, pointed to another prime example of I&I single product success: Sanofi and Regeneron’s Dupixent . A dual inhibitor of IL-4 and IL-13 signaling, Dupixent is approved in the U.S. to treat eight inflammation-driven diseases, including atopic dermatitis, chronic obstructive pulmonary disease and asthma. In the third quarter, Sanofi reported €4.2 billion ($4.8 billion), the first time the antibody has exceeded the €4 billion mark in a single quarter. Earnings AbbVie’s Immunology Dyad Dominates Again in Q3 Skyrizi and Rinvoq made nearly $7 billion combined, almost half of the company’s income for the quarter alone. October 31, 2025 · 2 min read · Dan Samorodnitsky Build a ‘Better Mousetrap’ While the pipeline-in-a-product strategy is leveraged across other therapeutic spaces—think Keytruda in oncology—I&I presents a unique opportunity, experts told BioSpace . “The key thing about immunology is that a lot of these diseases . . . they present with very, very different symptomatology, and what the cause of the disease is and what autoantibodies involved are all different, but there are centralized mechanisms that you can leverage with a single product,” said Myles Minter, biotech analyst and partner at William Blair. A company can prove safety in one indication, he continued, “and then expedite the development as a pipeline in a product in subsequent indications.” Further, Minter said, once these pathways are established, the opportunity exists to improve upon original drugs with next-generation models. “You’ve also got this pathway that’s been set by predecessor compounds, that the biology actually plays out. It’s just, can you do it in a better way? And that’s where we’re seeing all these next-generation therapies come through.” Minter offered the example of Roche’s Rituxan (rituximab), first approved for non-Hodgkin lymphoma in 1997, and for a variety of other cancers and inflammatory diseases since. Minter described Rituxan as “quite a brutal therapy.” He explained, “It will deplete your B cells, but it is efficacious when it works.” Now, on the B cell modulation side, Vertex and other companies are focused on candidates such as povetacicept that inhibit BAFF and APRIL—two targets expressed on the various B cells responsible for autoantibody production in many autoimmune diseases. Novartis’s ianalumab also targets the BAFF receptor. It’s a strategy that has worked before. Suvannavejh pointed out that Humira was not the first drug to block tumor necrosis factor (TNF)—it was just the most effective. Humira was preceded in the market by J&J’s Remicade and Amgen’s Enbrel, “but . . . it’s really Abbott and then AbbVie that kind of perfected the model, and I think they just had a better mousetrap for blocking TNF alpha.” The range of diseases that can be targeted in I&I is also quite broad, Minter noted. “Inflammation and immunology spans a lot of different indications, and it gives you an option to go either after very prevalent diseases,” such as atopic dermatitis and plaque psoriasis. “Or you can go into increasingly rare disease opportunities,” where he sees Vertex and Biogen heading with their respective pipelines. Of course, no matter how plentiful the opportunities—or the company’s cash on hand—it is important to be “somewhat capital efficient,” Minter said. “You can’t just put a drug into every single indication that comes in your head and do it all at once.” On that note, there are key indications the biggest players are prioritizing. Minter highlighted IgAN, the lead indication for povetacicept. Novartis won FDA approval last year for Fabhalta, the first complement inhibitor for the reduction of proteinuria in primary IgAN . Suvannavejh, meanwhile, pointed to atopic dermatitis, rheumatoid arthritis, psoriasis, asthma, chronic obstructive pulmonary disease (COPD) and ulcerative colitis. For Suvannavejh, the common theme between Humira and Dupixent and similar drugs is that they broadly target common pathways of inflammation across the skin, gastrointestinal and other organ systems. “There are X number of cellular cytokines and mediators of inflammation, and if you can find that widget that can block inflammation, then you have the potential of working in lots of different conditions,” he said, “because inflammation is everywhere.” Business 5 Biotechs Taking the Pipeline-in-a-Product Approach to Drug Development The platform strategy of using one molecule to target an underlying biological pathway to address many different diseases can be a goldmine for smaller companies. But it also has a unique set of challenges. August 20, 2025 · 10 min read · Tristan Manalac