Sutimlimab

核心导读：赛诺菲（Sanofi）Riliprubart（SAR445088），补体C1s抑制剂，在慢性炎性脱髓鞘多发性神经病（CIDP）II期展现积极疗效信号。本文复盘II期-III期潜在落差，分析开放标签II期偏倚、疾病安慰剂效应、入组人群差异，提炼自免罕见病临床开发启示。 🔬一、补体C1s靶点、Riliprubart分子与CIDP背景 补体经典通路是抗体介导自身免疫组织损伤的核心效应通路。C1复合物由C1q、C1r、C1s构成，C1q识别自身抗体形成的免疫复合物后，激活C1s蛋白酶；活化C1s依次剪切C4、C2，组装C3转化酶，驱动下游C3活化与膜攻击复合物（MAC）生成，介导髓鞘破坏与轴索损伤，这也是抗体介导周围神经损伤的经典机制。 Riliprubart（SAR445088）为选择性活化C1s抑制剂，人源化IgG4亚型单克隆抗体，仅阻断经典补体通路，保留凝集素通路、旁路补体通路完整。对比C5抑制剂，其理论优势在于不会全局关闭补体系统，有望降低荚膜细菌感染风险，这是该分子差异化设计核心逻辑。给药方式为皮下注射，具备居家给药潜力；开发适应症布局CIDP、抗体介导移植排斥等，曾在美国获得CIDP孤儿药资格认定。 慢性炎性脱髓鞘多发性神经病（Chronic Inflammatory Demyelinating Polyneuropathy, CIDP）是最常见慢性免疫介导周围神经病，患病率约2~5/10万，疾病特征为进行性或复发缓解型周围神经髓鞘脱失合并轴索损伤，临床表现四肢无力、感觉减退，重症患者丧失独立行走能力。一线标准治疗（Standard of Care, SoC）包括静脉免疫球蛋白（Intravenous Immunoglobulin, IVIg）、糖皮质激素、血浆置换；70%~80%患者可获得临床应答，但20%~30%患者对一线治疗应答不佳，约15%属于多线难治人群，存在明确未满足临床需求。 CIDP并非单一同质疾病，是一组异质性疾病谱，包含典型CIDP与多种变异亚型。不同患者损伤驱动通路存在巨大差异：部分患者损伤以体液免疫、补体激活为主；另一部分患者核心损伤由T细胞介导。靶点假说成立 ≠ 全部CIDP患者都存在经典补体通路驱动病变，这是理解该靶点临床转化风险最底层病理前提。既往神经根活检研究可在部分CIDP患者样本检出补体沉积，支撑C1s靶点开发假说；但组织补体沉积仅为相关性证据，无法直接证明抑制C1s即可带来稳定、可重复的临床功能获益。 🔬二、II期关键数据，MOBILIZE / VITALIZE III期试验规划完整事件 Riliprubart CIDP II期为开放标签、单臂多中心研究，分为Part A（24周核心治疗期）和Part B（延长至76周长期观察），入组包含标准治疗难治CIDP患者，研究数据在周围神经学会（Peripheral Nerve Society, PNS）年会披露。 Part A（24周）核心结果：难治性CIDP亚组（n=18），89%患者达到疾病改善或稳定，其中50%观察到临床功能改善；整体入组队列约52%患者出现优于基线的功能改善；治疗后神经丝轻链蛋白（Neurofilament Light chain, NfL，轴索损伤生物标志物）较基线下降35%，外周血经典补体活性持续被抑制。进入Part B延长阶段后，24周应答者中89%在76周维持疗效；安全性整体可耐受，最常见不良事件为头痛、疲劳、鼻咽炎，未观察到严重感染信号。生物标志物层面NfL下降与临床改善同步，支撑研发团队推进III期的确证计划。 基于该II期开放标签阳性数据，赛诺菲登记两项独立III期试验：MOBILIZE与VITALIZE，两个人群设计有明确区分： 1.MOBILIZE：目标入组标准治疗难治CIDP患者，研究设计为随机、双盲、安慰剂对照的确证试验；该试验登记启动，截至目前，企业未发布中期分析终止公告。本文复盘，是假设该II期单臂阳性信号无法在MOBILIZE随机对照试验（Randomized Controlled Trial, RCT）中重现，推演背后原因，属于临床开发风险复盘，不是对已发生失败事件的事后总结。 2.VITALIZE：入组正在接受IVIg维持治疗的CIDP患者，试验目标评估Riliprubart联合或替代IVIg的临床潜力；人群基线特征与MOBILIZE难治人群差异显著，是该分子CIDP管线另一独立验证队列。 该项目最核心矛盾点：小样本单臂开放标签II期，在难治亚组观察到较高应答率；但该阳性信号，在随机双盲安慰剂对照的确证试验中极有可能无法重复。在自免新药研发领域，单臂II期信号无法在RCT重复是非常普遍的失败模式；而CIDP这类波动性自免罕见病，会进一步放大假阳性风险。 🔬三、深度拆解：为什么开放标签II期容易高估疗效 开放标签单臂试验无安慰剂对照，受试者、研究者均知晓给药状态。在CIDP这类主要终点依赖功能评分、患者报告结局（Patient Reported Outcome, PRO）的神经免疫疾病，疗效高估效应会被显著放大，是多重偏倚叠加结果。 3.1 评估者与受试者主观偏倚 CIDP临床评估包含整体神经残疾复发和缓解量表（Inflammatory Rasch-built Overall Disability Scale, I-RODS）、肌力、行走功能等指标，大量评估维度带有主观属性。开放标签环境中，研究者更容易将微小、一过性的疾病波动判定为治疗应答；受试者知晓接受试验新药，疲劳、肢体麻木等主观主诉会出现安慰剂驱动正向偏移。这类偏倚在随机双盲安慰剂对照RCT中被严格控制，但在单臂开放标签II期完全无法剔除。 3.2 选择偏倚与小样本富集效应 II期样本量很小，难治亚组仅18例，整体队列规模有限。开放标签研究入组阶段，更容易纳入基线疾病活动度更高、自发改善概率更高的患者；而基线持续缓慢进展、轴索损伤不可逆的重症患者，入组意愿更低。小样本条件下，少数患者偶然的自发缓解就会显著拉高整体应答率，也就是阳性富集效应。II期观察到的高应答亚组，并不能代表真实世界全部难治CIDP人群。 3.3 背景治疗洗脱与疾病自然病程混杂 CIDP存在显著的既往治疗遗留效应。很多入组患者前期长期接受IVIg、激素治疗，即便进入研究后撤减原有治疗，既往免疫调节作用仍可维持数月。开放标签设计无法区分：患者功能改善，是C1s抑制带来的药物效应，还是原有标准治疗的延迟效应、疾病本身自然波动叠加。这是自免神经疾病II期研究最常见混杂因素。 3.4 生物标志物解读陷阱 II期观察到的外周血C1s通路抑制、NfL下降，仅属于靶点占位与药理活性证据，不等同临床获益证据。药物成功结合靶点、抑制通路，仅证明分子层面药理作用；靶标抑制到临床功能改善之间存在巨大转化鸿沟。部分患者体内补体通路被抑制，但髓鞘、轴索损伤已经固定，神经功能无法逆转。NfL下降可提示轴索损伤减轻，但在小样本开放标签研究，生物标志物变化同样受基线波动、选择偏倚干扰，不能单独作为临床疗效替代终点。 多重偏倚叠加，就会形成II期"亮眼阳性"假象。单臂开放标签研究适合安全性评估、靶点占位验证、给药方案探索、候选生物标志物筛选，但没有确证药物临床疗效的能力。 🔬四、CIDP疾病本身安慰剂效应、疾病波动特征 CIDP属于复发缓解或波动性进展疾病，疾病自发波动，是II期信号难以在RCT重复最核心的疾病底层因素，该特征在既往多款CIDP候选药物临床试验反复被证实。 第一，CIDP存在自发缓解现象。文献IVIg撤除试验数据显示，16%~55%患者停用免疫治疗后并未出现疾病恶化，部分患者进入长期疾病静息状态，即疾病"burn out（燃尽）"。开放标签随访周期内，一部分患者改善本身就是疾病自然转归，和试验药物无关。在无安慰剂对照组的II期，所有自发缓解案例全部计入药物应答；在MOBILIZE这类随机安慰剂对照试验中，安慰剂组同样会观察到可观比例稳定/改善，直接压缩药物与安慰剂之间疗效差值，造成无法达到主要终点的风险。既往利妥昔单抗CIDP的RIM-CIDP随机对照试验，出现高度相似现象：开放标签研究提示临床获益，但后续RCT未能证明其优于安慰剂，安慰剂组稳定/改善比例与治疗组接近，印证CIDP较高安慰剂效应与自发波动风险。 第二，CIDP疾病谱高度异质性。并非所有CIDP患者组织损伤都由经典补体通路驱动；部分患者发病核心是T细胞介导细胞毒性损伤，经典通路激活只是伴随现象。II期小样本恰好富集补体高活化亚型，因此观察到应答；若III期MOBILIZE扩大入组，纳入更广泛难治人群，大量非补体驱动患者入组，整体人群药物效应会被稀释。靶点生物学假说成立，但是仅在特定亚型人群成立；入排标准缺少配套生物标志物筛选，在宽泛定义CIDP人群开展RCT，失败风险极高。 第三，功能终点评估时间窗口难题。CIDP肌力、行走功能改善进程缓慢，短期随访微小波动非常普遍。II期24周评估窗口下，一过性改善会被判定为应答；RCT需要稳定、持续临床获益，一过性波动不能满足确证试验终点判定标准。 🔬五、全球C1s抑制剂自免管线全景 C1s作为经典补体通路上游靶点，在抗体介导自身免疫病持续受到产业关注；管线分为已获批资产、临床阶段单抗、下一代C1s靶向分子，各分子适应症选择、临床阶段、差异化设计差异显著。 药物名称 研发企业 核心适应症 关键特征与进展 Sutimlimab 赛诺菲（Sanofi） 冷凝集素病（Cold Agglutinin Disease, CAD） 全球首款获批C1s抑制剂；CAD病理高度依赖经典补体通路介导红细胞破坏，终点为血红蛋白等客观实验室指标，主观评估干扰小，成功转化验证C1s靶点在抗体介导溶血疾病的价值 Riliprubart（SAR445088） 赛诺菲（Sanofi） CIDP、抗体介导移植排斥 皮下注射C1s单抗；CIDP管线规划两项III期试验MOBILIZE（难治人群）、VITALIZE（IVIg维持人群）；提示靶点在异质性强、主观终点为主的神经自免领域转化风险显著抬升 Claseprubart（DNTH103） Dianthus Therapeutics 重症肌无力、CIDP、多灶性运动神经病 靶向活化C1s，带YTE半衰期延长改造，皮下给药；管线还布局双功能分子DNTH312，同时结合C1s与B细胞活化因子（BAFF/APRIL），同时阻断补体+B细胞活化 早期C1s分子 多家生物技术公司 各类抗体介导自免病 包含部分小分子C1s蛋白酶抑制剂，大多处于临床前或I期概念验证阶段，尚未进入II期 横向对比可见C1s靶点转化存在明确适应症选择性：疾病机制越单一、终点为客观实验室指标（溶血、血细胞计数），转化成功率越高；疾病异质性强、主要终点依赖神经功能主观评分、疾病存在自发波动，临床开发失败风险显著上升。Riliprubart项目潜在风险，不是否定C1s靶点本身，而是提示开发者：靶点有效性不能跨疾病直接外推。 🔬六、行业教训：自免罕见病，II期开放标签数据 不能作为推进III期的充分证据 Riliprubart项目是自免罕见病临床开发极具代表性的案例，可以用来复盘开放标签II期阳性信号的解读原则，对靶点验证、II期决策、试验设计、人群分层提供明确启示。 6.1 区分"概念验证信号"和"确证疗效证据" 开放标签单臂II期的核心价值，是评估安全性、确认靶点占位、初步探索给药方案、筛选潜在应答生物标志物，而不是确认药物临床疗效。在波动型、主观终点为主的自免罕见病，单臂阳性仅提示"值得继续探索"，不能直接作为启动大规模、高成本III期RCT的唯一依据。当单臂II期样本量小、无安慰剂对照、终点大量依赖主观评分，必须充分评估假阳性风险。资源允许前提下，优先开展小样本随机对照IIa期，设置安慰剂对照，提前过滤开放标签带来的虚假疗效信号，避免直接投入III期巨额开发成本。 6.2 重视疾病异质性，提前开发伴随筛选生物标志物 CIDP属于疾病谱而非单一疾病。未来补体、FcRn、BTK等靶点在CIDP开发，应避免宽泛入组，优先依靠生物标志物富集目标人群：例如基线神经根补体沉积、血清补体活化产物、特定自身抗体阳性亚组，仅在靶点驱动人群验证疗效。Riliprubart II期阳性很可能来自补体高活化小亚组；若III期宽泛入组，则会出现效应稀释，带来试验失败风险。对于异质性自免罕见病，缺少伴随筛选标志物的广谱入组，属于高风险开发策略。 6.3 区分靶标抑制与临床获益，谨慎解读生物标志物 药物实现靶点抑制、NfL下降等生物标志物改善，仅为药理活性证据，不等于真实临床功能获益。生物标志物可以作为次要支持终点；但神经免疫疾病中，不能替代稳定、可重复的功能终点。II期阶段，需要观察生物标志物变化是否和持续临床应答稳定相关，而不是仅看短期一过性同步改变。 6.4 临床试验终点设计适配疾病波动特征 CIDP这类复发缓解疾病，试验终点应优先选择持续应答，排除短期一过性改善；样本量计算阶段，预先纳入安慰剂效应、自发缓解率。既往多个神经免疫药物在CIDP、重症肌无力研发折戟，均存在低估安慰剂效应的问题。罕见病人群外部历史对照价值有限，历史对照队列和本次试验基线人群、背景治疗存在不可控差异，无法替代同期安慰剂对照。 6.5 管线决策分层，做好风险对冲 赛诺菲针对Riliprubart设置两个人群独立III期试验（MOBILIZE难治人群，VITALIZE IVIg维持人群），本身是风险对冲设计。即便MOBILIZE无法达到终点，也不等于终止整个CIDP项目；VITALIZE入组人群基线疾病特征不同，仍具备独立探索价值。该项目提示：同一适应症不同亚组，应拆分为独立临床假设，不可由一个亚组II期阳性直接外推至全部人群。 🔬七、结语 Riliprubart项目，是理解自免罕见病早期临床信号真伪的典型案例。开放标签II期观察到亮眼疗效信号，在小样本、无对照、主观终点叠加疾病自发波动的场景下，极易高估药物真实疗效。在冷凝集素病这类机制清晰、客观生物标志物成熟疾病中，C1s抑制剂Sutimlimab已经证明临床价值；但当靶点进入CIDP这类高度异质性、功能终点依赖主观评估的神经免疫疾病，靶点假说成立，不等于临床转化成功。 对自免研发团队而言，Riliprubart项目给出核心准则：开放标签II期数据仅作为早期线索，启动确证性III期前，尽可能增设随机对照IIa期、引入生物标志物富集策略，充分评估疾病安慰剂效应与自然病程。罕见病领域，临床研究者、投资人很容易因为巨大未满足临床需求，放大早期阳性信号；但临床开发必须尊重疾病异质性，严格区分药理活性与真实临床获益，避免被单臂试验亮眼数据误导，在III期投入巨额资金后遭遇失败。新药研发的本质，不只是追求好看的II期数据，而是甄别真假疗效信号，找到能够稳定获益的患者亚群。 数据来源 1. Sanofi. Riliprubart (SAR445088) Phase 2 open-label study in CIDP. Peripheral Nerve Society Annual Meeting, 2024. 2. Parry GJ, et al. Evaluation and treatment of refractory chronic inflammatory demyelinating polyradiculoneuropathy. Journal of the Neurological Sciences. 3. Van den Bergh P, et al. EAN/PNS guideline on diagnosis and treatment of CIDP. European Journal of Neurology, 2021. 4. Dyck PJB, et al. Rituximab versus placebo for CIDP after IVIg withdrawal. Neurology. 5. Complement classical pathway inhibition in antibody-mediated autoimmune diseases. Annual Review of Immunology, 2024. 6. Dianthus Therapeutics. Claseprubart (DNTH103) clinical development overview. Corporate pipeline document. 7. Röth A, et al. Sutimlimab for cold agglutinin disease. New England Journal of Medicine, 2020. 免责声明：本文基于公开临床试验登记信息、学术年会壁报、文献及企业管线披露资料整理。MOBILIZE试验尚未公布失败结果，全文为基于II期数据局限性的推演复盘，不是事后失败总结。仅为行业学术复盘讨论，不构成任何投资建议、临床诊疗建议或用药指导。临床试验结果具有不确定性，药物有效性和安全性仍需确证性RCT验证。 III 期顶线阳性！VC005 会是自免 AD 的国产答案吗？ 狼疮新药以后都要做生物标志物富集试验吗？从一个IIb的成与败说起 三项III期全达标却主动终止！Amlitelimab折戟AD：OX40赛道真的走不通了？ 破局干燥综合征：BAFF/APRIL 通路之争与 B 细胞靶向疗法的二十年救赎 从肿瘤到自免的跨界革命：BTK抑制剂如何重塑自身免疫疾病治疗格局 自免 License-out 潮：15 亿美元纸面对价背后，中国小分子出海的收益与暗礁 自免领域并购的底层逻辑是什么？回溯: 武田40 亿美元收购 Zasocitinib：重金押注 TYK2 罕见自身免疫领域-CIDP全球跨国药企研发进展 BTK 抑制剂在 SLE 屡战屡败：B 细胞指标显著下降，为什么临床终点却无法达标？ 辉瑞PF‑06835375（抗CXCR5单抗）：系统性红斑狼疮Ⅰ期临床的机制、数据与靶点定位 诺华 ianalumab（BAFF 受体单抗）干燥综合征 III 期数据复盘：无 DMT 的干燥综合征，终于等到获批药物？ 自免领域深度| IgAN肾病管线扎堆：四大机制路径，谁的临床证据最具确证性？ Nektar Therapeutics自免领域布局深度分析 | 聚焦Treg稳态调控的差异化管线格局 系统性红斑狼疮（SLE）二十余年新药临床试验复盘：大量 II 期阳性、III 期折戟，SLE 临床试验固有的难点到底在哪里？ 国产JAK抑制剂扎堆申报：选择性提升后，心血管与血栓风险能否真正缓解？ 2型炎症被过度泛化了吗？AD、哮喘、鼻窦炎共享通路，为何跨适应症拓展屡屡碰壁？ 2026 年 1-10 月，全球自身免疫领域 BD总额超 240 亿美元 , 正在改写哪些底层逻辑？ 自免临床深度|斑块银屑病终点内卷：PASI90/PASI100、停药维持，我们是否在过度追逐极致皮损清除？ 不清除 B 细胞也能控制自身免疫？Obexelimab 登 NEJM，IgG4-RD III 期阳性，CD19×FcγRIIb 改变 B 细胞治疗格局 2026年9月全球自身免疫疾病领域创新药研发月报 Dupilumab 专利悬崖倒计时：赛诺菲下一代自免管线缺口，BD 能补上吗？ 从脓疱银屑病到全身自免：IL-36R抑制剂能否打开下一个黄金赛道？ 警钟敲响！自免 CD19 CAR‑T 遭遇死亡事件：从奇迹个案到工业化临床，我们交了什么学费？ 自免临床的安慰剂陷阱：为什么II期亮眼，III期频频翻车？ FcRn：自身抗体驱动自免的广谱靶点？全球8款核心管线深度对比 BMS 守城、武田进攻、Alumis 突围：三款口服 TYK2 抑制剂同台拆解  Clinical-stage Biotech Beeline Medicines：BMS 分拆自免新锐，TLR7/8 赛道的机遇与不确定性 2026年8月全球跨国药企特应性皮炎（Atopic Dermatitis, AD）在研临床管线进展 2026年8月中国创新药企 系统性红斑狼疮（SLE）在研临床管线进展 截止2026 年 8 月 PROTAC 在自身免疫疾病领域的全球在研临床管线进展 【版权说明】：本公众号欢迎个人分享朋友圈或大群，但媒体或机构权转载需本公众号授权.

Scientists have identified the genetic cause behind the mysterious AnWj blood group antigen, solving a puzzle that began in 1972 and establishing a new blood group system called MAL. The discovery could make it much easier to find extremely rare AnWj-negative patients and donors and protect them from potentially dangerous transfusion reactions.More than half a century after scientists first encountered a mysterious marker on human red blood cells, researchers finally traced it to its genetic source. The breakthrough established MAL as a human blood group system and gave doctors a new way to identify the exceptionally rare people whose blood lacks the AnWj antigen. The work was led by scientists at NHS Blood and Transplant in Bristol, including researchers from the International Blood Group Reference Laboratory (IBGRL), together with colleagues at the University of Bristol. Their findings solved a puzzle dating back to 1972 and could help prevent dangerous transfusion reactions in a small number of patients. Although most people are familiar with the ABO and Rh blood groups, those are only part of a much larger biological system. Red blood cells carry hundreds of different molecules on their surfaces. Many of these molecules act as antigens, markers that the immune system can recognize. For most transfusions, ABO and Rh compatibility receive the most attention. But in patients with unusual antibodies or rare blood types, matching some of these lesser-known antigens can become crucial. A Blood Marker Found in More Than 99.9% of People The AnWj antigen was discovered in 1972, but for decades scientists did not know which gene produced it or which protein carried it on red blood cells.[1] More than 99.9% of people are AnWj positive. For the tiny minority who are AnWj negative, however, the distinction can matter enormously. If an AnWj negative person develops antibodies against AnWj and then receives AnWj positive blood, those antibodies can attack the transfused red blood cells. In some circumstances, that can trigger a potentially serious transfusion reaction. There are also two very different reasons someone can lack the antigen. In most cases, AnWj expression appears to be suppressed because of an underlying hematological disorder or certain cancers.[2] Much more rarely, a person is born without the antigen because of an inherited genetic change. Only a handful of people with this inherited form had ever been identified, making the mystery especially difficult to investigate. The Genetic Clue Was Hidden in MAL To find the source, the researchers turned to whole exome sequencing. This technique examines the portions of DNA that contain instructions for making proteins, allowing scientists to search across thousands of genes for unusual variants shared by affected individuals. The analysis pointed unexpectedly to the MAL gene. The researchers found that people with the inherited AnWj negative phenotype carried homozygous deletions affecting MAL. Homozygous means that the relevant change was present in both copies of the gene, one inherited from each parent. The MAL gene produces a small membrane protein called Mal. When the team examined red blood cells, people who were AnWj positive produced the full-length Mal protein on their cells, while it was missing from AnWj negative cells. Five genetically AnWj negative individuals were included in the investigation, including members of an Arab Israeli family.[3] The samples also included blood donated in 2015 by the woman who had been the first AnWj negative person identified in the 1970s. The researchers did not stop at finding a genetic association. They needed to demonstrate that Mal really was responsible for the antigen. When scientists introduced the normal MAL gene into laboratory cells, the cells became reactive with AnWj antibodies. Introducing the altered form did not produce the same response. Additional experiments showed that Mal was both necessary and sufficient for expression of the AnWj antigen. MAL Becomes an Official Blood Group System Those results provided the evidence needed to establish MAL as a distinct blood group system, with AnWj as its defining antigen. The International Society of Blood Transfusion later formally reported MAL as ISBT 047. MAL was one of four blood group systems ratified during the period covered by the organization's 2026 terminology report, alongside ER, CD36 and ATP11C. That designation is more significant than simply adding another name to a list. For something to qualify as a blood group system, researchers must connect an antigen to a defined genetic and molecular basis. MAL was the 47th officially recognized blood group system at the time. The field has continued to move quickly since then. In September 2026, the International Society of Blood Transfusion announced JAMA as the 49th blood group system, illustrating how the genetic map of human blood is still being expanded. Why the Discovery Matters for Transfusions Knowing the gene behind AnWj gives blood specialists something they did not previously have: a direct genetic way to search for people who inherit AnWj-negative blood. Genotyping tests can now be designed to identify rare patients and donors carrying the relevant MAL changes. These tests can potentially be incorporated into existing blood group genotyping systems. That matters because finding compatible blood for someone with an antibody against a marker present in more than 99.9% of people can be extraordinarily difficult. The need is not merely theoretical. Earlier clinical reports have shown that anti-AnWj antibodies can cause hemolytic transfusion reactions, in which transfused red blood cells are destroyed by the recipient's immune system. More recent cases have underscored just how complicated the situation can become. In 2026, researchers reported a 75-year-old man with severe anemia and an anti-AnWj autoantibody. Compatible blood was unavailable, so physicians ultimately transfused unmatched red blood cells after weighing the risks. Genetic testing showed that his MAL gene was normal, supporting the conclusion that his antibody was acquired rather than caused by the rare inherited MAL deficiency. He did not experience a hemolytic transfusion reaction in that case. Another 2026 case involved a patient with high-grade B-cell lymphoma and a complement-binding anti-ANWj autoantibody. After incompatible transfusions were followed by signs of red blood cell destruction, clinicians used sutimlimab, a drug that blocks part of the immune complement pathway. The patient's laboratory measurements improved, although the researchers stressed that the complicated case and short treatment period prevent firm conclusions about the treatment's effectiveness. It was reported as the first use of sutimlimab for this particular type of anti-AnWj-associated hemolysis. Together, these cases highlight an important distinction. Some people are AnWj negative because of inherited MAL changes, while others can lose AnWj expression because of disease and develop an antibody against a marker their cells previously carried. A Mystery That Took Decades to Crack Louise Tilley, Senior Research Scientist, IBGRL Red Cell Reference at NHS Blood and Transplant, said: "The genetic background of AnWj has been a mystery for more than 50 years, and one which I personally have been trying to resolve for almost 20 years of my career. It represents a huge achievement, and the culmination of a long team effort, to finally establish this new blood group system and be able to offer the best care to rare, but important, patients. "The work was difficult because the genetic cases are very rare. We would not have achieved this without exome sequencing, as the gene we identified wasn't an obvious candidate and little is known about Mal protein in red cells. Proving our findings was challenging, and we appreciate the help of all our collaborators, and the patients, without whom we would not have got to this point." One reason the mystery endured for so long was simply the rarity of inherited AnWj negative blood. With so few known cases, researchers had very little genetic material from affected people to compare. The Mal protein itself also offered few obvious clues. It is a very small protein embedded in cell membranes and has been associated with processes involving membrane organization and cellular transport. Nothing immediately pointed to it as the carrier of a long mysterious red blood cell antigen. Gene Editing Helped Confirm the Answer Ash Toye, Professor of Cell Biology in the School of Biochemistry and Director of the NIHR Blood and Transplant Research Unit in red cell products at the University of Bristol, said: "It's really exciting we were able use our ability to manipulate gene expression in the developing blood cells to help confirm the identity of the AnWj blood group, which has been an outstanding puzzle for half a century. This development will help identify these rare donors and help patients in the future." Manipulating gene expression allowed the researchers to test cause and effect rather than simply observe that a genetic variant happened to occur in AnWj negative people. By changing which genes cells expressed and then testing whether AnWj appeared, the scientists could build a much stronger case that MAL was the missing piece. Nicole Thornton, Head of IBGRL Red Cell Reference at NHS Blood and Transplant, said: "Resolving the genetic basis for AnWj has been one of our most challenging projects. "There is so much work that goes into proving that a gene does actually encode a blood group antigen, but it is what we are passionate about, making these discoveries for the benefit of rare patients around the world. "Now genotyping tests can be designed to identify genetically AnWj-negative patients and donors. Such tests can be added to the existing genotyping platforms." The official ISBT blood group database now lists the reference MAL allele along with the null allele associated with the AnWj negative phenotype, turning what was once an unexplained serological curiosity into a genetically defined blood group system. Human Blood Is Far More Complicated Than ABO The MAL story also illustrates how much complexity is hidden behind the familiar letters A, B, AB and O. Blood groups are defined by inherited differences in molecules on red blood cells. These differences often have little noticeable effect in everyday life. They become important when the immune system encounters red blood cells carrying an antigen it recognizes as foreign, particularly during transfusion or pregnancy. That is why rare blood group research can have an outsized clinical impact despite involving very few people. If a patient has an antibody against an antigen carried by nearly everyone else, locating compatible donor blood can require specialized laboratories, rare donor registries and sometimes international cooperation. Dr. Tim Satchwell, Senior Lecturer at UWE Bristol, who contributed to the study whilst a Research Fellow at the University of Bristol, said: "Mal is a very small protein with some interesting properties which made it difficult to identify and meant we needed to pursue multiple lines of investigation to accumulate the proof we needed to establish this blood group system. Being able to combine our expertise to finally achieve this has brought the whole team a lot of satisfaction." For more than 50 years, AnWj was a blood antigen without a known genetic home. The identification of MAL changed that, giving researchers a molecular explanation, clinicians a path toward better genetic testing, and rare patients a better chance of being identified before a difficult transfusion becomes an emergency. Notes