A Parallel-group Treatment, Phase 2a, Multicenter, Randomized, Double-blind, Placebo-controlled Umbrella Study to Evaluate the Efficacy and Safety of Frexalimab, SAR442970, and Rilzabrutinib in Participants Aged 16 to 75 Years With Primary Focal Segmental Glomerulosclerosis (FSGS) or Minimal Change Disease (MCD)

This is a parallel, Phase 2a, double-blind, 6-arm study for the treatment of primary focal segmental glomerulosclerosis (FSGS) or primary minimal change disease (MCD).
The purpose of this study is to measure the change in proteinuria and its impact on the rates of remission of nephrotic syndrome with frexalimab, SAR442970, or rilzabrutinib compared with placebo in participants with primary FSGS or primary MCD aged 16 to 75 years.
Study details for each participant include:
The study duration will be up to 76 weeks. The treatment duration will be 24 weeks. There will be up to 18 visits.

开始日期2024-12-19

申办/合作机构

Sanofi

CTIS2023-504358-36-00

/ Recruiting临床3期

Randomized, double-blind, Phase 3 study comparing efficacy and safety of frexalimab (SAR441344) to teriflunomide in adult participants with relapsing forms of multiple sclerosis - EFC17919A

开始日期2024-10-17

申办/合作机构

Sanofi-Aventis Recherche & Développement SA

CTR20241809

/ Recruiting临床3期

两项独立的在复发型多发性硬化成人受试者中对比 frexalimab（SAR441344）与特立氟胺的疗效和安全性的随机、双盲、Ⅲ 期研究的主方案

主要：评估 frexalimab 与 14 mg 日剂量特立氟胺相比在复发型 MS 受试者中的疗效（根据 ARR 评估）。次要：评估 frexalimab 与特立氟胺相比，对残疾恶化、MRI 病灶、认知表现、生理机能和生活质量的疗效。评价 frexalimab 在复发型 MS 受试者中的安全性和耐受性。评价 frexalimab 在复发型 MS 受试者中的药效学。评价 frexalimab 在复发型 MS 受试者中的药代动力学

开始日期2024-06-24

申办/合作机构

Sanofi-Aventis Recherche & Développement SA

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100 项与 Frexalimab 相关的临床结果

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100 项与 Frexalimab 相关的转化医学

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100 项与 Frexalimab 相关的专利（医药）

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项与 Frexalimab 相关的文献（医药）

2024-02-15·The New England journal of medicine1区 · 医学

Inhibition of CD40L with Frexalimab in Multiple Sclerosis

1区 · 医学

Article

作者: Truffinet, Philippe ; Dufek, Michal ; Giovannoni, Gavin ; Staikov, Ivan ; Wallstroem, Erik ; Cutter, Gary ; Granziera, Cristina ; Vermersch, Patrick ; Kalbus, Oleksandr ; Bejuit, Raphael ; Saubadu, Stephane ; Mao-Draayer, Yang ; Djukic, Biljana

BACKGROUND:

The CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a second-generation anti-CD40L monoclonal antibody being evaluated for the treatment of multiple sclerosis.

METHODS:

In this phase 2, double-blind, randomized trial, we assigned, in a 4:4:1:1 ratio, participants with relapsing multiple sclerosis to receive 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or the matching placebos for each active treatment. The primary end point was the number of new gadolinium-enhancing T1-weighted lesions seen on magnetic resonance imaging at week 12 relative to week 8. Secondary end points included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety. After 12 weeks, all the participants could receive open-label frexalimab.

RESULTS:

Of 166 participants screened, 129 were assigned to a trial group; 125 participants (97%) completed the 12-week double-blind period. The mean age of the participants was 36.6 years, 66% were women, and 30% had gadolinium-enhancing lesions at baseline. At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 (95% confidence interval [CI], 0.1 to 0.4) in the group that received 1200 mg of frexalimab intravenously and 0.3 (95% CI, 0.1 to 0.6) in the group that received 300 mg of frexalimab subcutaneously, as compared with 1.4 (95% CI, 0.6 to 3.0) in the pooled placebo group. The rate ratios as compared with placebo were 0.11 (95% CI, 0.03 to 0.38) in the 1200-mg group and 0.21 (95% CI, 0.08 to 0.56) in the 300-mg group. Results for the secondary imaging end points were generally in the same direction as those for the primary analysis. The most common adverse events were coronavirus disease 2019 and headaches.

CONCLUSIONS:

In a phase 2 trial involving participants with multiple sclerosis, inhibition of CD40L with frexalimab had an effect that generally favored a greater reduction in the number of new gadolinium-enhancing T1-weighted lesions at week 12 as compared with placebo. Larger and longer trials are needed to determine the long-term efficacy and safety of frexalimab in persons with multiple sclerosis. (Funded by Sanofi; ClinicalTrials.gov number, NCT04879628.).

Frontiers in Immunology

The role of microglia in multiple sclerosis: implications for treatment with Bruton’s tyrosine kinase inhibitors

Review

作者: Van Wijmeersch, Bart ; Pozzilli, Carlo ; Magyari, Melinda ; Vermersch, Patrick ; Popescu, Veronica ; Hartung, Hans-Peter ; Airas, Laura ; Deisenhammer, Florian ; Berger, Thomas ; Grigoriadis, Nikolaos ; Oreja-Guevara, Celia ; Pugliatti, Maura ; Zakaria, Magd

Background:

Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS), characterized by inflammation and neurodegeneration. The pathophysiology of MS, especially its progressive forms, involves various cellular components, including microglia, the primary resident immune cells of the CNS. This review discusses the role of microglia in neuroinflammation, tissue repair, and neural homeostasis, as well as their involvement in MS and explores potential therapeutic strategies targeting microglial function.

Methods:

A literature search conducted in August 2023 and updated in March 2025, using the PubMed database, focused on articles relating to microglia and MS published in 2018–2025. Additionally, ongoing clinical trials of Bruton’s tyrosine kinase (BTK) inhibitors were identified through the ClinicalTrials.gov website in November 2023 and updated in March 2025.

Results:

Microglia are highly adaptive and exhibit various functional states throughout different life stages and play critical roles in neuroinflammation, tissue repair, and neural homeostasis. Their altered activity is a prominent feature of MS, contributing to its pathogenesis. Imaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) provide insights into microglial activity in MS. BTK inhibitors and other novel treatments for MS, including masitinib and frexalimab, show promise in modulating microglial function and influencing the disease progression rate.

Conclusions:

The multifaceted roles of microglia in CNS development, immune surveillance, and particularly in the pathogenesis of MS highlight the potential of targeting microglial functions in MS treatment. Emerging research on the involvement of microglia in MS pathophysiology offers promising avenues for developing novel therapies, especially for progressive MS, potentially improving patient outcomes in this debilitating disease.

Annals of Medicine and Surgery

Frexalimab (SAR441344) as a potential multiautoimmune disorder tackling mAB targeting the CD40-CD40L pathway undergoing clinical trials: a review

Review

作者: Karamat, Riyan I. ; Mirza, Aeliya ; Akilimali, Aymar ; Naeem, Silla ; Ahmad, Bilal ; Fatima, Faiza ; Fatima, Tehreem ; Shahid, Iqra

Autoimmune disorders exhibit intricate pathology. Their mechanisms are complex, which attenuates the need for novel therapeutic interventions. Frexalimab, a potent monoclonal antibody targeting the dysregulated CD40-CD40L pathway, stands out as a formidable weapon against the assault of inflammation and tissue devastation. Diverse electronic databases were searched using relevant keywords to extract data on the role of Frexalimab in combating various autoimmune diseases. This review highlights Frexalimab’s efficacy in improving various disability indicators of relapsing multiple sclerosis (RMS), alleviating fatigue in primary Sjögren’s syndrome (PSJS), and improving glycemic control in diabetic patients. Across multiple trials, its favorable safety profile has proven its superiority over first-generation drugs in minimizing side effects. Indeed, Frexalimab has become a harbinger of hope in the fight against autoimmune diseases and has pioneered a unique and unchallenging way for tackling complex autoimmune diseases in the clinical realm, however, further large-scale trials are needed to establish its therapeutic benefits across different autoimmune conditions.

101

项与 Frexalimab 相关的新闻（医药）

2025-09-08

·靶点圈

从实验室到临床：TNF/TNFR 超家族药物研发的传奇之路（综述大盘点）

01 TNF和TNFR超家族的生物学基础家族组成肿瘤坏死因子(TNF)和肿瘤坏死因子受体(TNFR)在免疫细胞的促炎和凋亡信号传导中起关键作用，其信号失调与多种疾病相关。TNF超家族(TNFSF)含18个人类基因，编码20多种蛋白(包括异源三聚体)，与29种TNF受体超家族(TNFRSF)成员通过40多种配体-受体相互作用模式进行信号传递。 ● TNF超家族的结构特征：TNFSF成员以肿瘤坏死因子同源结构域为支架，通过原体组装形成同源/异源三聚体(发挥功能的受体结合单位)。TNFSF的三聚体结构具有三个受体结合位点(由两个相邻亚基构成)，可诱导受体聚集。当配体与受体结合后，受体胞质域排列形成信号复合物，招募衔接蛋白。 ● TNFR超家族的结构特征：TNFRSF成员多是由多个二硫键构成受体胞外域的细长梯状结构，还含有半胱氨酸富集域(CRDs)，构成配体结合部分，不同成员的CRDs数量不同(1-6个)。多数TNFRSF成员发挥生物活性需要多个三聚体复合物以晶格状排列聚集。部分TNFRSF成员含有前配体组装域(PLAD)，可限制未结合配体的受体取向以防止自发激活，还可能有助于受体信号单元的多聚化。信号机制 ● 促存活通路：依赖含E3泛素连接酶的TNFR相关因子(TRAF)衔接蛋白，招募形成cIAP-TRAF-E3泛素连接酶复合物，降解抑制剂并释放活性丝氨酸激酶(如NIK、IKKα、IKKβ)，激活NF-κB、MAPK等通路，调控细胞增殖与存活。 ● 促凋亡通路：依赖死亡结构域(DD)衔接蛋白(如Fas相关死亡域)，启动胱天蛋白酶水解级联反应，诱导凋亡、坏死性凋亡并释放炎症细胞因子(如IL-1β)。图1 T细胞上的共刺激TNFRSF成员以及它们的配体和代表性信号通路生理与病理作用 ● 生理作用：参与先天性和适应性免疫系统的发育与协调，对免疫细胞的发育、活化、增殖、存活等过程起着重要调控作用，如T细胞活化、B细胞存活、淋巴器官形成等。 ● 病理作用：异常激活可能会导致炎症、癌症和自身免疫疾病等，表现为免疫活性失控，如抗原呈递细胞(APCs)、T细胞和B细胞的反应过度，以及TNFSF的过量产生作用于组织细胞直接驱动病理过程。同时，由于其在调控先天性和适应性免疫中的核心作用，TNFRSF的激活可能增强癌症中的免疫保护相关的免疫应答。图2 TNFSF成员在不同APC子集上的上下文相关角色 02 TNF/TNFR超家族的分子机制 TNF信号轴 ● 机制：TNF可由多种细胞在炎症条件下产生，通过TNFR1和TNFR2发挥作用。 ①TNFR1：广泛表达，激活后能诱导细胞死亡、免疫细胞激活及多种炎症相关分子表达，还可通过引发细胞死亡间接促进炎症； ②TNFR2：主要在特定细胞表达，其激活可促进T/B淋巴细胞增殖、存活和分化，在Tregs中与免疫耐受和抗炎功能相关。 ● 疾病关联：TNF在先天和体液免疫反应中不可或缺，但慢性炎症中其异常表达是多种IMIDs的病理标志，如类风湿关节炎(RA)、炎症性肠病(IBD)患者血清及病变组织中TNF水平升高与疾病严重程度相关，TNFRSF1A基因多态性与银屑病、溃疡性结肠炎(UC)和克罗恩病(CD)有关。 TL1A信号轴 ● 机制：TL1A作为一种炎症细胞因子，主要由树突状细胞、巨噬细胞等抗原呈递细胞在炎症刺激下表达，通过与DR3结合激活NF-κB、PI3K等通路，促进T细胞效应功能和纤维化相关细胞因子分泌，引发炎症和细胞凋亡。同时，它还存在可溶性DcR3作为诱饵受体调节其功能。 ● 疾病关联：TL1A-DR3相互作用在T细胞中起共刺激信号作用，与多种自身免疫性疾病发病机制相关。在UC和CD患者中，其血清和肠道组织中的表达水平升高，还可通过多种途径促进炎症、纤维化及组织重塑。此外，TNFSF15基因多态性与IBD、银屑病等相关。 CD40/CD40L信号轴 ● 机制：CD40在多种免疫细胞如B细胞、树突状细胞、单核细胞等表面表达；CD40L是其天然三聚体配体，主要在活化T细胞、血小板等细胞上表达。二者结合后，CD40胞内结构域募集TRAF，激活NF-κB、MAPK、Jak3/STAT3和PI3K/Akt等信号通路，促进细胞活化、增殖、分化，释放细胞因子和炎症介质，参与免疫应答和炎症反应。 ● 疾病关联：CD40/CD40L信号与多种自身免疫性疾病相关，其基因多态性与多种疾病关联。在RA、系统性红斑狼疮(SLE)和IBD患者中，其表达水平异常，阻断该信号可缓解疾病症状。 OX40/OX40L信号轴 ● 机制：OX40在激活的CD4+和CD8+T细胞上表达；OX40L在APCs等细胞上表达。二者结合后，能激活NF-κB、ERK、PI3K、AKT等信号通路，促进T细胞存活、增殖，以及IL-2、IL-4、IL-5、IL-17、IFN-γ等细胞因子的分泌，同时抑制CTLA-4等免疫抑制受体，提升免疫应答。此外，OX40信号在Tregs中会损害其抑制功能。 ● 疾病关联：OX40的基因多态性(TNFSF4)与多种IMIDs相关，在SLE、银屑病和特应性皮炎(AD)、哮喘等疾病中，OX40/OX40L的表达异常，阻断该信号在疾病治疗方面展现出潜力。 BAFF/BAFF-R信号轴 ●机制：BAFF由多种免疫细胞产生，与BAFF-R等受体结合，促进B细胞存活、成熟和抗体产生，通过非经典NF-κB信号通路传导信号。 ● 疾病关联：BAFF/BAFF-R信号在RA和SLE等自身免疫性疾病的发病和进展中起关键作用，如在这些疾病患者中，BAFF或BAFF-R的表达水平升高，与疾病活动度和病理变化相关。图3 焦点TNF/TNFR分子的分子信号机制及其拮抗作用的抗炎益处表1 TNF/TNFR超家族基因在焦点炎症性疾病中的代表性GWAS关联 03 靶向TNF/TNFR的药物研发进展 TNF拮抗剂 ● 作用机制：通过中和TNF或阻断其与TNFR1/TNFR2的结合，抑制下游炎症信号(如NF-κB通路)，减少免疫细胞过度活化和细胞因子释放。 ● 已获批的TNF拮抗剂 ①英夫利昔单抗(Infliximab，Remicade，1998年获批)：首个抗TNF单克隆抗体，是人类化IgG1单克隆抗体，获批用于CD、银屑病、RA、UC。 ②阿达木单抗(Adalimumab，Humira)：为人类IgG1单克隆抗体，通过拮抗TNF发挥作用，已获批用于CD、银屑病、RA、UC等多种IMIDs。 ③依那西普(Etanercept，Enbrel)：由人TNFR2的胞外域与人类IgG1抗体的Fc部分融合而成，可拮抗TNF，获批用于银屑病和RA。 ④戈利木单抗(Golimumab，Simponi)：是人类IgG1单克隆抗体，获批用于UC、RA，同时在CD的Ⅱ期临床试验中开展研究。 ⑤赛妥珠单抗聚乙二醇(Certolizumabpegol，Cimzia)：是聚乙二醇化的人源化IgG1单克隆抗体的抗TNF的F(ab)片段，已获批用于CD、银屑病、RA，且在UC的Ⅱ期临床试验中进行研究。 ⑥奥扎利珠单抗(Ozoralizumab，Nanozora)：为人类化三价双特异性纳米抗体，由两个抗TNF-α的VHH和一个抗HSA的VHH组成，已在日本获批用于RA。图4 TNF抑制剂的结构和FDA批准时间表 ●处于研发阶段的TNF拮抗剂 ①ABBV-3373：是一种阿达木单抗-GRM类固醇偶联物(ADC)，具有TNF拮抗和糖皮质激素受体调节双重作用，目前处于Ⅱ期临床试验阶段，用于治疗RA。 ②SAR441566：属于小分子TNF拮抗剂，处于Ⅱ期临床试验，用于RA和银屑病的治疗。其作用机制是稳定可溶性TNF三聚体的不对称构象，使其仅能结合三个可能的TNFR1受体结合位点中的两个，从而限制受体聚集和信号传导，在胶原诱导关节炎的小鼠模型中，展现出剂量依赖性的疾病症状抑制作用。 ● TNF拮抗剂的临床应用与挑战自首次获批25年多以来，TNF抑制剂一直是控制RA、IBD和银屑病等疾病最广泛使用且成功的抗炎疗法之一，能显著降低类风湿关节炎的关节炎症、银屑病的皮肤损伤及克罗恩病的肠道炎症，改善患者生活质量。但当前的TNF拮抗剂存在一些局限性，如原发性无应答率较高，在CD患者中，抗TNF治疗初始诱导的原发性无应答率在试验中为20%-40%，且在抗TNF治疗开始后的12个月内，23%-46%的患者会出现应答丢失，7%-25%的患者会停止治疗；还可能增加机会性感染风险、引发免疫原性导致抗药抗体形成和疗效逐渐丧失，以及诱发自身抗体等。这些局限性也推动着新型TNF拮抗剂的研发。 TL1A拮抗剂 ● 作用机制：TL1A拮抗剂通过阻断TL1A与DR3的相互作用，抑制相关信号通路的激活，从而减少炎症细胞因子的分泌，减轻炎症反应，并可能抑制纤维化进程。比如在肠道炎症中，可降低促炎细胞因子如TNF、IFN-γ的产生，缓解肠道炎症，还能减少成纤维细胞的活化，抑制胶原合成，改善肠纤维化。 ● 研发进展全球处于临床阶段的TL1A靶点药物有12款，其中单靶点药物9款。处于临床II期的有辉瑞的RG6631(PF-06480605/RVT-3101)、默沙东的Tulisokibart(MK-7240/PRA-023)、梯瓦制药的TEV-48574。 ①Tulisokibart(PRA023)：为一种人源化IgG1抗TL1A单抗。在克罗恩病(CD)的Ⅱa期试验中，临床缓解率为49%，内镜应答率26%，目前已启动UC的Ⅲ期试验。 ②TEV-48574：属于人IgG1抗TL1A单抗，已启动UC和CD的2期试验招募，但此前其哮喘2期研究因未达主要目标而终止。 ③PF-06480605(RVT-3101)：抗TL1A单克隆抗体，在溃疡性结肠炎(UC)的Ⅱb期试验中，14周临床缓解率达32%，显著高于安慰剂(12%)，且能降低肠道纤维化相关标志物表达。 ● 临床意义炎症性肠病(IBD)影响全球约600-800万人，美国约200万人，现有疗法仅有10-15%的患者病情缓解。TL1A拮抗剂为IBD患者提供了新的治疗选择。此外，TL1A拮抗剂还可能对其他免疫和纤维化疾病，如类风湿关节炎、特应性皮炎、系统性红斑狼疮、哮喘、银屑病等有治疗潜力。 ● 市场前景 IBD药物市场规模较大且呈增长趋势，2021年美国IBD药物市场约为150亿美元。TL1A靶点药物受到众多制药巨头青睐，如辉瑞、罗氏、默沙东、赛诺菲等纷纷布局。罗氏以高额价格收购RVT-3101，默沙东收购Prometheus-Biosciences获得PRA023，赛诺菲与梯瓦合作开发TEV-48574，这一系列动作显示出TL1A拮抗剂在未来医药市场具有较大的发展潜力。 CD40/CD40L拮抗剂 ● 作用机制：CD40L在活化T细胞上表达，与APCs表面的CD40结合后促进免疫细胞活化。靶向药物通过阻断该相互作用，抑制过度免疫反应。 ● 研发进展 ①达匹利珠单抗(Dapirolizumabpegol)：一种聚乙二醇化的抗CD40LF(ab’)片段，用于治疗SLE，在早期临床试验中显示出良好疗效，目前正在进行3期试验。 ②Frexalimab：一种新型抗CD40L单克隆抗体，能阻断CD40/CD40L细胞通路，且不会导致淋巴细胞耗竭。在治疗MS的2期试验中取得积极结果，显著减缓了复发性MS患者的疾病活动，目前已启动3期临床试验，同时也在进行针对1型糖尿病患者的2期临床研究。 ③达佐利单抗(Dazodalibep)：一种非抗体生物拮抗剂，由两个能结合CD40L的Tn3蛋白与人血清白蛋白融合而成，在RA的Ⅱ期临床试验中，显著降低了疾病活动度，且不良事件与安慰剂组相当，耐受性良好。 ④Abiprubart：一种CD40拮抗单克隆抗体，可阻断CD40-CD40L相互作用介导的B细胞激活，在RA的Ⅱ期试验中达到了主要终点。 ⑤Ravagalimab：一种CD40拮抗剂单克隆抗体，在UC的Ⅱ期试验中进行了测试。 ● 临床意义 CD40/CD40L通路的过度激活与多种自身免疫性疾病相关，如SLE患者血清中可溶性CD40L水平升高，且与疾病活动度密切相关；RA患者血清中CD40表达水平上升，与ACPA增加及疾病活动度显著相关。CD40/CD40L拮抗剂通过抑制该通路，有助于减少炎症介质释放，调节免疫细胞功能，延缓关节损伤进展，为自身免疫性疾病患者提供了新的治疗选择。在SLE治疗中，可降低自身抗体滴度，减少疾病发作；在RA治疗中，能改善疾病活动度；在MS治疗中，可减少大脑病变，降低组织损伤。 ● 面临挑战早期CD40L抗体在临床试验中出现过血栓栓塞并发症，这是由于抗体对CD40L和血小板上的Fc受体(FcRs)双重结合，导致血小板激活引发。不过，后续开发的Fc沉默或缺乏Fc结构域的CD40/CD40L拮抗剂，如Frexalimab、Dapirolizumab-pegol等，在安全性方面有了明显改善，在临床试验中未显示出血栓栓塞活动迹象。此外，自身免疫性疾病具有异质性，部分由T细胞独立机制驱动的疾病，对抗CD40L治疗可能反应不佳。 OX40/OX40L拮抗剂 ● 作用机制：OX40/OX40L拮抗剂可抑制二者的结合，阻断上述信号通路的激活，进而降低炎症反应和免疫应答强度。比如靶向OX40的单克隆抗体可抑制和减少表达OX40的活化T细胞数量；靶向OX40L的单克隆抗体不耗竭已活化T细胞，而是通过与OX40L结合，阻止其与OX40相互作用，阻断T细胞活化。 ● 研发进展 ①罗卡替尼(Rocatinlimab)：一种全人源、IgG1型抗OX40单克隆抗体，通过抑制OX40，抑制T细胞增殖、扩增和记忆T细胞形成。通过抗体依赖的细胞毒性(ADCC)清除OX40+T细胞，在特应性皮炎中使湿疹面积和严重程度指数(EASI)降低50%以上。 ②阿美利单抗(Amlitelimab)：一种非T细胞耗竭、全人源的IgG4型抗OX40L单克隆抗体，可与OX40L结合，阻断其与OX40的相互作用，还可抑制OX40L的反向信号传导，阻断2型和Th1/17/22炎症。 ● 临床意义 OX40/OX40L信号通路的异常激活与多种自身免疫性疾病相关，如在AD患者的皮肤中，OX40/OX40L表达上调，促进IL-4驱动的Th2辅助细胞分化。OX40/OX40L拮抗剂通过抑制该通路，有助于减少炎症介质释放，调节免疫细胞功能，为自身免疫性疾病患者提供了新的治疗选择。在AD治疗中，可改善皮肤症状，如降低湿疹面积和严重程度指数，清除或减轻皮肤症状。 ● 面临挑战作为TNFR超家族成员，OX40靶点抗体存在一定风险，这类抗体如果引起靶点交联，会短时内极大地激活T细胞，引起细胞因子释放综合征，严重时危及生命。因此，筛选具有阻断活性而非激动活性的抗体、降低体内交联风险、开展试验充分评估风险等，是确保OX40拮抗剂未来长期安全性的重点与难点。 BAFF/BAFF-R拮抗剂 ● 作用机制：BAFF/BAFF-R拮抗剂通过阻断BAFF与BAFF-R的相互作用，抑制这些信号通路的激活，减少B细胞的活化和自身抗体的分泌，进而减轻自身免疫反应。 ● 研发进展 ①贝利尤单抗(Benlysta，2011年获批)：首个获批用于SLE治疗的抗BAFF单克隆抗体，能抑制B细胞存活和分化为浆细胞，降低患者血清IgG和自身抗体水平。 ②泰它西普(Telitacicept，中国获批)：一种能中和BAFF和增殖诱导配体(APRIL)的Fc融合蛋白，用于SLE和IgA肾病，减少蛋白尿和肾功能损伤。 ③Ianalumab：一种BAFF-R拮抗的人IgG1单克隆抗体，通过ADCC作用裂解B细胞并阻断BAFF-R信号，在SLE的Ⅱ期研究中表现良好，降低了疾病活动度和自身抗体滴度，目前正在进行Ⅲ期研究。 ④Rozibafuspalfa：一种同时拮抗BAFF和诱导性T细胞共刺激配体(ICOSL)的双特异性抗体，正在进行SLE的Ⅱb期研究。 ⑤Povetacicept：一种与TACI融合的Fc蛋白，可中和BAFF和APRIL，已进入自身免疫性肾脏疾病的Ib/2a期研究。 ● 临床意义 BAFF/BAFF-R信号通路在SLE、RA等自身免疫性疾病的发病机制中起关键作用。SLE患者血清BAFF水平与疾病活动度和自身抗体水平相关，RA患者滑膜组织中BAFF-R表达升高。BAFF/BAFF-R拮抗剂为这些疾病的治疗提供了新方向，能有效减少自身抗体和免疫复合物的产生，缓解系统性炎症和组织损伤。在SLE治疗中，可降低疾病活动度，改善肾脏等器官功能；在RA治疗中，有望减轻关节炎症和损伤。 ● 面临挑战尽管BAFF/BAFF-R拮抗剂在临床试验中取得了一定成果，但仍面临一些挑战。部分患者对药物的应答存在差异，并非所有患者都能获得理想的治疗效果。长期使用这些拮抗剂可能会影响正常的B细胞功能，增加感染等不良反应的风险。此外，药物的研发和生产成本较高，可能限制其广泛应用。表2 靶向TNF/TNFR的药物(2 期及以上) 表3 TNFS 或TNFRSF在自身免疫和炎症中的临床靶向 04 其他潜在靶点图5 其他FDA批准的基于TNFSF的疗法 CD30/CD30L ● 机制：CD30与CD30L的信号传导是活化T细胞和专职抗原呈递细胞(APCs)的主要促存活和促炎信号。 ● 疾病关联：CD30在类风湿关节炎(RA)、系统性红斑狼疮(SLE)、特应性皮炎(AD)和哮喘等多种IMIDs中表达上调，其基因多态性与湿疹相关。 ● 研发进展： ①MK-8690(PRA-052)：一种人抗CD30L单克隆抗体，目前处于Ⅰ期临床试验阶段，用于炎症性肠病(IBD)治疗，旨在评估其安全性和药理学特性。 4-1BB(TNFRSF9) ● 机制：4-1BB在活化T细胞上表达，其共信号作用可促进T细胞存活、增殖和细胞因子产生。 ● 潜在应用：虽然4-1BB激动剂主要用于癌症治疗，但基于其在免疫调节中的作用，研究探索了通过4-1BB选择性“同种免疫防御受体”(ADR)设计细胞疗法，以选择性清除致病性淋巴细胞，在自身免疫病和移植物抗宿主病(GvHD)中诱导免疫耐受，相关临床前研究已显示潜力。图6 结合4-1BB信号传导的免疫治疗策略 RANK/RANKL ● 机制：成骨细胞表达的膜结合RANKL与RANK结合，通过相互作用调控髓系细胞分化为破骨细胞，是骨吸收和稳态的主要驱动因素。 ● 疾病关联：在RA中，RANK/RANKL信号与骨侵蚀密切相关。 ● 研发进展： ①地诺单抗(Denosumab，2010年获批)：抗RANKL单克隆抗体，用于骨质疏松症等治疗，在日本还被批准用于抑制RA相关的骨侵蚀。Ⅲ期研究显示，其能显著减少RA患者的关节破坏进展。 BCMA(TNFRSF17) ● 机制：BAFF和APRIL与BCMA结合，驱动浆细胞存活，BCMA在成熟B细胞(尤其是长寿骨髓浆细胞和浆母细胞)上高表达。 ● 疾病关联：与SLE等自身免疫病中自身抗体的产生相关。 ● 研发进展： ①Descartes-08(RNA-based自体BCMA特异性CAR-T)：用于SLE治疗，处于Ⅱ期评估阶段； ②CD19-BCMA双靶点CAR-T疗法：在狼疮性肾炎(LN)患者的Ⅰ期研究中显示出显著疗效，可清除自身抗体并实现症状缓解。图7 治疗癌症的新型TNFRSF疗法表4 TNFRSF在癌症中的临床靶向抗体发现服务 & 产品 01 羊驼免疫&骆驼免疫—自建现代化养殖农场 02 万亿级天然抗体库产品—轻松DIY科研抗体 03 配套产品—助您轻松搭建基因工程抗体平台关于仁域生物成都仁域生物成立于2019年1月，是一家专注基因工程抗体技术和天然抗体库开发的公司，拥有优化的噬菌体展示抗体库技术和现代化的骆驼/羊驼养殖免疫基地。公司主营业务： ◆ 全人源/纳米抗体定制；◆ 噬菌体展示抗体库定制； ◆ 多肽/多肽库定制；◆ 羊驼/骆驼免疫服务； ◆ 文库相关产品经销商。 protocol 获取 / 产品咨询邮箱｜find@renyubio.com 电话｜19136178673 地址｜成都市经开区科技产业孵化园关注我们，小编将持续更新相关内容～参考文献 Watts TH, Yeung KKM, Yu T, Lee S, Eshraghisamani R. TNF/TNFR Superfamily Members in Costimulation of T Cell Responses-Revisited. Annu Rev Immunol. 2025 Apr;43(1):113-142. Croft M, Salek-Ardakani S, Ware CF. Targeting the TNF and TNFR superfamilies in autoimmune disease and cancer. Nat Rev Drug Discov. 2024 Dec;23(12):939-961. Veerasubramanian PK, Wynn TA, Quan J, Karlsson FJ. Targeting TNF/TNFR superfamilies in immune-mediated inflammatory diseases. J Exp Med. 2024 Nov 4;221(11):e20240806. Müller D. Targeting Co-Stimulatory Receptors of the TNF Superfamily for Cancer Immunotherapy. BioDrugs. 2023 Jan;37(1):21-33.

蛋白降解靶向嵌合体免疫疗法临床终止

2025-08-29

·EndPoints

FDA approves BTK inhibitor that’s key to Sanofi’s immunology strategy

The FDA approved Sanofi’s BTK inhibitor that the French drugmaker acquired in its $3.7 billion buyout of Principia Biopharma. The company said Friday that the regulators cleared rilzabrutinib in a rare disease called immune thrombocytopenia, or ITP. The drug is branded as Wayrilz. The wholesale acquisition cost for Wayrilz will be $17,500 a month, which is before discounts, rebates or patient assistance programs, a Sanofi spokesperson said. Wayrilz is part of a larger effort at Sanofi to become the leading immunology pharma company. Sanofi has unveiled or acquired a handful of programs targeting immunological conditions in recent years, and the company expects Wayrilz to produce between €2 billion and €5 billion in annual peak sales. So far, Sanofi’s strategy hasn’t always led to success. The company was forced to shelve studies of another drug from Principia called tolebrutinib in 2023 after trials were put on hold . The drug continued to be dogged by safety concerns despite positive efficacy results in a multiple sclerosis trial that read out last year. Tolebrutinib had been Principia’s lead drug at the time Sanofi acquired the company in 2020. Another program called itepekimab underwhelmed in a COPD study earlier this year. And even the path for Wayrilz has been bumpy. The drug failed an atopic dermatitis study in 2023. Sanofi’s immunology pipeline also includes amlitelimab, an OX40L drug from Kymab that’s currently in Phase 3 studies for atopic dermatitis; lunsekimig, an anti-IL-13/TSLP program with a Phase 2 readout in asthma expected next year; and frexalimab, a CD40L-targeting therapy that’s expecting Phase 2 lupus data in the second half of 2026. “Our current and evolving portfolio within immunology and immunoscience more broadly really explores the multifaceted nature of key neurologic nodes within the immune system,” Sanofi CSO Mike Quigley told Endpoints News in an interview ahead of the decision. As for Wayrilz, ITP is a rare autoimmune disorder that leads to low platelet counts and an increased risk of bleeding and bruising. Quigley estimates there are about 100,000 ITP patients in the US. In addition to ITP, Sanofi is continuing to study Wayrilz in asthma, chronic hives, IgG4-related disease and other rare diseases, though these studies are early and no readouts are expected until 2027. Editor’s note: This story was updated to add the drug’s wholesale acquisition cost.

免疫疗法并购临床3期上市批准临床2期

2025-08-11

·FierceBiotech

Novartis scores double phase 3 win in Sjögren\'s syndrome, succeeding where rivals failed

Novartis hailed the win as the “first ever global phase 3 trials to demonstrate statistically significant reduction in disease activity for Sjögren\'s disease.”\n Novartis may have abandoned one Sjögren\'s syndrome asset this year, but it looks like the drugmaker has a winner on its hands with another candidate.The Swiss pharma had been evaluating ianalumab, a dual-mechanism, B-cell-depleting antibody that targets the protein BAFF-R, in a pair of phase 3 studies dubbed Neptunus 1 and 2, which in total enrolled 779 patients with the systemic autoimmune disease.Both studies hit their primary endpoint of demonstrating an improvement in disease activity as measured on the EULAR Sjögren\'s syndrome disease activity index at 52 weeks compared to placebo, Novartis announced in an Aug. 11 release. The drug was also well tolerated and demonstrated a favorable safety profile, according to the pharma.The company hailed the win as the “first ever global phase 3 trials to demonstrate statistically significant reduction in disease activity for Sjögren\'s disease.” For now, Novartis is holding back the data for a future medical conference, while referencing plans to take the results to global regulators with the aim of bringing the first targeted treatment for the autoimmune disease to market.“Sjögren\'s disease is a serious, progressive, systemic autoimmune disease, often unrecognized or misdiagnosed with a significant detrimental impact to quality of life, with very limited treatment options and an established unmet need,” Novartis Chief Medical Officer Shreeram Aradhye, M.D., said in the release.“Both phase 3 trials demonstrate that ianalumab improves disease activity in patients with Sjögren\'s disease,” Aradhye added. “These phase 3 studies mark a significant milestone. We look forward to engaging with health authorities to discuss these findings in the near future.”It’s a big win for Novartis, which started the year dropping its anti-CD40 antibody iscalimab after becoming doubtful of its competitive profile. That left ianalumab as Novartis’ last and best hope for the disease.Ianalumab had already shown \"meaningful differences in patients with this very difficult-to-treat disease” in phase 2, Novartis executives pointed out at the time.Iscalimab was only the latest Big Pharma prospect to fail to make the grade in Sjögren\'s. Last year, Sanofi crossed off Sjögren’s from the list of targeted indications for its CD40L monoclonal antibody frexalimab after seeing phase 2 efficacy data, while, more recently, Kiniksa Pharmaceuticals ended work on its own Sjögren\'s prospect abiprubart. While Novartis had always sounded positive about the potential of ianalumab in the automimmune disease, the therapy has faced its own clinical setbacks. Only last month, the company reported that the B-cell-depleting antibody had failed to hit the efficacy threshold in a phase 2 study for a painful skin condition called hidradenitis suppurativa.Ianalumab\'s story begins with Novartis’ collaboration with MorphoSys, before the Big Pharma went on to buy the biotech last year. The therapy is also being investigated for other B cell-driven autoimmune diseases like immune thrombocytopenia, systemic lupus erythematosus, lupus nephritis, warm autoimmune hemolytic anemia and diffuse cutaneous systemic sclerosis.

$Novartis scores double phase 3 win in Sjögren\'s syndrome, succeeding where rivals failed$

临床3期临床2期临床结果临床失败

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
继发进展型多发性硬化	临床3期	美国	Sanofi	2023-12-27
继发进展型多发性硬化	临床3期	中国	Sanofi	2023-12-27
继发进展型多发性硬化	临床3期	日本	Sanofi	2023-12-27
继发进展型多发性硬化	临床3期	阿根廷	Sanofi	2023-12-27
继发进展型多发性硬化	临床3期	澳大利亚	Sanofi	2023-12-27
继发进展型多发性硬化	临床3期	比利时	Sanofi	2023-12-27
继发进展型多发性硬化	临床3期	巴西	Sanofi	2023-12-27
继发进展型多发性硬化	临床3期	保加利亚	Sanofi	2023-12-27
继发进展型多发性硬化	临床3期	加拿大	Sanofi	2023-12-27
继发进展型多发性硬化	临床3期	智利	Sanofi	2023-12-27

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临床结果

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04879628 (NEWS) 人工标引	临床2期	复发性多发性硬化	129	Frexalimab high dose	醖繭願淵壓夢積顧積積(衊選鏇夢鬱醖蓋獵壓衊) = 鏇範獵鬱襯鹽製鹹築鹽餘獵膚壓餘憲顧築鏇醖 (糧膚網夢繭鑰鹽範壓醖 )	积极	2024-07-05
				Frexalimab low dose	醖繭願淵壓夢積顧積積(衊選鏇夢鬱醖蓋獵壓衊) = 願網艱餘範夢鹹積鹹鹹餘獵膚壓餘憲顧築鏇醖 (糧膚網夢繭鑰鹽範壓醖 )
NCT04879628 (Phase 2 trial, EAN2024)	临床2期	-	129	Frexalimab-high dose	選範憲衊淵襯壓鬱獵觸(醖選醖繭淵選鬱淵壓憲) = 廠獵鬱觸顧願壓醖鏇襯製範願願選壓襯積艱醖 (蓋範鹹簾憲壓壓觸憲獵 )	积极	2024-06-28
				Frexalimab-low dose	選範憲衊淵襯壓鬱獵觸(醖選醖繭淵選鬱淵壓憲) = 獵鏇鏇夢膚膚選餘衊蓋製範願願選壓襯積艱醖 (蓋範鹹簾憲壓壓觸憲獵 )
NCT04879628 (phase 2 trial, EAN2024)	临床2期	复发性多发性硬化 plasma neurofilament light chain	129	Frexalimab high dose	憲願構網鹽獵襯膚醖餘(壓鏇鹽齋窪衊鑰願獵製) = 積願製衊積鬱艱製淵膚壓觸獵構簾齋淵鹹積顧 (顧齋遞獵鑰淵鹹艱窪艱, 2.0)	积极	2024-06-28
				Frexalimab low dose	憲願構網鹽獵襯膚醖餘(壓鏇鹽齋窪衊鑰願獵製) = 遞選鬱餘衊廠淵範餘蓋壓觸獵構簾齋淵鹹積顧 (顧齋遞獵鑰淵鹹艱窪艱, 1.7)
NCT04879628 (Corporate Publications) 人工标引	临床2期	多发性硬化症	125	frexalimabfrexalimab 1200 mg	廠願構壓窪醖鹽鹹獵夢(顧襯蓋鏇積襯衊衊構憲) = 夢鬱壓鏇鬱廠鹽製夢膚鹹鑰鹹鑰醖夢夢鹹艱鹹 (夢壓製鹽糧餘窪範網製 ) 更多	积极	2024-04-17
				frexalimab 300 mgfrexalimab 300 mg	廠願構壓窪醖鹽鹹獵夢(顧襯蓋鏇積襯衊衊構憲) = 齋窪窪壓鏇淵衊鏇襯艱鹹鑰鹹鑰醖夢夢鹹艱鹹 (夢壓製鹽糧餘窪範網製 ) 更多
AAN2024	N/A	复发性多发性硬化	-	Frexalimab high-dose	-	-	2024-04-09
				Frexalimab low-dose	夢廠蓋鏇構遞鏇遞鏇壓(鹹鹽壓築窪壓醖鑰鏇鹽) = 餘艱簾製繭齋醖鑰淵膚齋糧糧鑰構廠繭衊鏇膚 (衊範壓淵鏇憲糧願遞淵, 1.95)
AAN2024	N/A	复发性多发性硬化	-	Frexalimab high dose	醖艱獵膚憲鑰膚醖憲膚(構選膚淵遞蓋淵蓋蓋壓) = 鏇網壓構構鹹膚簾艱獵憲選選艱鏇齋齋襯鏇憲 (壓膚簾積齋餘廠壓齋艱 )	-	2024-04-09
				Frexalimab low dose	醖艱獵膚憲鑰膚醖憲膚(構選膚淵遞蓋淵蓋蓋壓) = 鹹鹽積築蓋窪積窪觸鹹憲選選艱鏇齋齋襯鏇憲 (壓膚簾積齋餘廠壓齋艱 )
NCT04879628 (Literature \| Pubmed \| N Engl J Med) 人工标引	临床2期	多发性硬化症	129	frexalimab 300 mg	鏇窪衊觸簾膚醖遞鬱鏇(衊顧觸廠窪齋製選壓壓) = 憲鑰壓製範獵簾繭遞壓構簾繭鹹廠壓網夢鬱衊 (膚淵顧餘構襯壓窪觸鏇, 0.1 ~ 0.6)	积极	2024-02-15
				frexalimab 1200 mg	鏇窪衊觸簾膚醖遞鬱鏇(衊顧觸廠窪齋製選壓壓) = 蓋築夢襯鹽遞積壓憲壓構簾繭鹹廠壓網夢鬱衊 (膚淵顧餘構襯壓窪觸鏇, 0.1 ~ 0.4)
NCT04879628 (GlobeNewswire) 人工标引	临床2期	复发性多发性硬化	129	frexalimab (high-dose)	糧窪衊繭廠蓋觸餘壓糧(蓋餘憲鹹壓繭製獵衊觸) = 鑰夢簾鬱鹽齋築淵憲積膚蓋夢繭窪網膚鹽顧衊 (餘淵醖遞網襯壓憲糧繭, -62 ~ -97) 达到更多	积极	2023-05-31
				placebo (high-dose)	-