评价使用DZP作为标准治疗药物的辅助治疗是否能够长期改善中重度疾病活动度的临床相关症状评价使用DZP作为标准治疗药物的辅助治疗是否能够快速改善中重度疾病活动度的临床相关症状评价使用DZP作为标准治疗药物的辅助治疗是否能够长期控制疾病活动度评价使用DZP作为标准治疗药物的辅助治疗是否能够实现和维持治疗达标目的：使用低/可接受剂量的皮质类固醇即可长期保持低疾病活动度评价使用DZP作为标准治疗药物的辅助治疗是否能够改善疾病活动度（通过临床实践中常用的疾病状态数值评分量表进行判定）评价使用DZP作为标准治疗药物的辅助治疗是否能够达到复合主要终点各组成部分的评分改善评价使用DZP作为标准治疗药物的辅助治疗是否能够达到替代终点应答评价使用DZP作为标准治疗药物的辅助治疗是否能够达到对其他关键次要终点提供支持的终点评价使用DZP作为标准治疗药物的辅助治疗的安全性和耐受性

开始日期2024-12-04

申办/合作机构

优时比贸易（上海）有限公司

NCT06617325

/ Recruiting临床3期

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Dapirolizumab Pegol in Study Participants With Moderately to Severely Active Systemic Lupus Erythematosus

The purpose of this study is to evaluate the ability of dapirolizumab pegol (DZP) as an add-on treatment to standard of care (SOC) medication to achieve clinically relevant long term improvement of moderate to severe disease activity.

开始日期2024-11-21

申办/合作机构

UCB Biopharma SRL

NCT04976322

/ Enrolling by invitation临床3期

A Multicenter, Open-Label Extension Study to Assess the Long-Term Safety and Tolerability of Dapirolizumab Pegol Treatment in Study Participants With Systemic Lupus Erythematosus

The purpose of this study is to evaluate long-term safety and tolerability of dapirolizumab pegol treatment.

开始日期2021-07-27

申办/合作机构

UCB Biopharma SRL

100 项与 Dapirolizumab pegol 相关的临床结果

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100 项与 Dapirolizumab pegol 相关的转化医学

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100 项与 Dapirolizumab pegol 相关的专利（医药）

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项与 Dapirolizumab pegol 相关的文献（医药）

2025-04-01·NEUROSCIENCE

Tangeretin enhances sedative activity of diazepam in Swiss mice through GABAA receptor interaction: In vivo and in silico approaches

Article

作者: Mia, Emon ; Ansari, Irfan Aamer ; Islam, Md Amirul ; Al Hasan, Md Sakib ; Saifuzzaman, Md ; Islam, Md Torequl ; Bhuia, Md Shimul ; Ansari, Siddique Akber ; Akbor, Md Showkoth ; Chowdhury, Raihan ; Yana, Noshin Tasnim ; Husain, Zakir

The citrus peel flavonoid tangeretin (TAN) has diverse biological activities, including antioxidant, anti-inflammatory, antitumor, hepatoprotective, and neuroprotective effects. This study investigates the sedative effects of TAN, in Swiss albino mice using in vivo and in silico approaches. TAN (10 and 20 mg/kg, i.p.) was administered alone and in combination with diazepam (DZP, 2 mg/kg, i.p.) and flumazenil (FLU, 0.1 mg/kg, i.p.) to evaluate its impact on thiopental sodium (TS)-induced sleep, locomotor activity, and dark-light behavior. Results demonstrated that TAN at 10 mg/kg significantly (p < 0.05) reduced sleep onset latency and increased sleep duration, with a synergistic effect observed when combined with DZP. In locomotor activity tests, TAN dose-dependently decreased the distance traveled, while the combination with DZP further enhanced this effect. Dark-light tests revealed that TAN increased dark residence time, indicating potential anxiolytic properties. Molecular docking studies showed that TAN binds to the GABA_A receptor (α1 and β2 subunits) with a binding affinity of -6.6 kcal/mol, suggesting its interaction with GABAergic pathways. Pharmacokinetic analysis indicated high intestinal absorption and compliance with Lipinski's rule of five, with a favorable safety profile (LD₅₀ = 5000 mg/kg). Overall, TAN enhances the sedative effects of DZP through GABA_A receptor modulation, highlighting its potential as a natural sedative agent. Further research should explore the long-term effects, bioavailability, blood-brain barrier permeability, and synergistic interactions of TAN, with comprehensive in vitro studies and clinical trials needed to validate its potential as a natural sedative.

2025-04-01·ANALYTICA CHIMICA ACTA

Multiplex immunochromatographic assay based on triple-color aggregation-induced emission fluorescent microspheres with good biocompatibility for the simultaneous detection of veterinary drugs in aquatic products

Article

作者: Zhang, Ganggang ; Lai, Xiaocui ; Zhang, Gan ; Su, Liu ; Liu, Cong ; Lai, Weihua ; Deng, Shengliang ; He, Weihua

BACKGROUND:

The simultaneous presence of multiple veterinary drug residues in a single sample poses a significant challenge for food safety analysis. Compared with traditional single-target detection, multiplex detection can not only provide richer sample information to raise the detection efficiency and reduce the possibility of false positives and omissions, but also decrease sample volume, shorten detection time, and lower costs. The luminance of aggregation-induced emission fluorescent microspheres (AIEFMs) can be enhanced by loading more fluorophores. The AIEFMs exhibit more advantages such as bright colors, excellent monodispersity, and high photostability, making them widely applicable in food safety.

RESULTS:

We successfully developed a multiplex immunochromatographic assay (ICA) using triple-color AIEFMs as signal labels for the simultaneous detection of three veterinary drugs: chloramphenicol (CAP), diethylstilbestrol (DES), and diazepam (DZP). AIEFMs with good biocompatibility were synthesized via a simple and quick one-pot method based on the self-aggregation of AIEgens and the coating of metal-polyphenol network formed through the coordination of proanthocyanidin and Fe³⁺ in a tetrahydrofuran/water mixed solution. The as-prepared AIEFMs were rapidly conjugated with antibodies to synthesize AIEFM probes without any coupling reagent, and the multiplex AIEFMs-ICA was established for the detection of CAP, DES, and DZP. Under optimal conditions, the detection limits for CAP, DES, and DZP were 1.67, 410, and 5 pg/mL, respectively. The average recoveries of these veterinary drugs in fish and shrimp samples ranged from 85.40 % to 113.15 %, demonstrating the reliability and stability of the multiplex AIEFMs-ICA.

SIGNIFICANCE:

The multiplex AIEFMs-ICA exhibited excellent signal output capacity, high specificity, and remarkable sensitivity. In brief, the developed multiplex AIEFMs-ICA shows great potential in the on-site detection of veterinary drugs and other targets.

2025-04-01·TALANTA

An organic-inorganic polyacrylamide-based surface imprinted quantum dots for the impedimetric and voltammetric detection of diazepam in saliva with smartphone readout

Article

作者: Daeid, Niamh Nic ; Adeniyi, Kayode Omotayo ; Adegoke, Oluwasesan ; Yang, Zhugen ; Achadu, Ojodomo J ; Oyinlola, Kayode

Diazepam (DZP) is a muscle-relaxing, anxiety-relieving sedative drug; nonetheless, it is also an addictive drug that may be abused. This work reports on the development of a novel electrochemical nanosensor for diazepam using SiO₂-encapsulated-3-mercaptopropionic acid-capped AuZnCeSeS quantum dots (QDs) overcoated with a molecularly imprinted polymer (MIP) on screen-printed carbon electrodes (SPCEs). Electrochemical, spectroscopic and electron microscopic characterization of the nanomaterial and modified electrode surface was carried out and is reported herein. Specifically, electrochemical characterization of the QDs/SPCE using cyclic voltammetry (CV) revealed that the QDs exhibit a higher electrode surface area whilst electrochemical impedance spectroscopy (EIS) characterization demonstrated a lower charge transfer resistance (R_ct). To fabricate the electrochemical nanosensor, firstly, alloyed AuZnCeSeS QDs were synthesized in the organic phase and thereafter capped with 3-mercaptopropionic acid (MPA) via a ligand exchange reaction. The MPA-AuZnCeSeS QDs were encapsulated in a SiO₂ layer to form a SiO₂-MPA AuZnCeSeS QDs system. The QDs were drop-casted onto SPCEs to form a SiO₂-MPA AuZnCeSeS QDs/SPCE transducer interface. Organic based acrylamide, used as a functional monomer, was electropolymerized via CV on the QDs/SPCE in the presence of the diazepam template with ethylene glycol dimethacrylate as a crosslinker and 2,2'-azobis(2-methylpropionitrile) as an initiator. Under optimum experimental conditions, DZP was detected using EIS and square wave voltammetry (SWV). Using a portable potentiostat and a hand-held smartphone-based potentiostat, DZP was quantitatively detected in saliva using the MIP@QDs/SPCE with a limit of detection (LOD) of 2.3 μM and 2.7 μM, respectively. The LOD for DZP from SWV analysis was 1.0 μM.

项与 Dapirolizumab pegol 相关的新闻（医药）

2025-03-27

·靶点圈

从机制到临床：CD40/CD40L通路药物为癌症和自身免疫病治疗带来颠覆性变革

1 仁域 CD40/CD40L靶点概述 1 CD40的分子结构：CD40是I型膜糖蛋白，基因位于染色体20q11-13，属于肿瘤坏死因子受体(TNFR)超家族的共刺激成员，需形成三聚体来实现最佳信号传导。在人类中，它有62个氨基酸的胞质尾、22个氨基酸的跨膜结构域和173个氨基酸的胞外结构域，胞外结构域含有4个半胱氨酸富集域(CRDs)，可参与寡聚化和配体结合。存在膜结合型(mCD40)和可溶性(sCD40)两种形式。sCD40能够作为CD40的天然拮抗剂，通过干扰CD40/CD40L的相互作用发挥作用。图1 CD40及其配体CD40L的结构域结构 2 CD40L的分子结构：CD40L是II型膜糖蛋白，又名CD154，位于X染色体Xq26.3，属于肿瘤坏死因子超家族(TNFSF)。在人类中，包含22个氨基酸的胞质尾、24个氨基酸的跨膜结构域和215个氨基酸的胞外结构域，胞外区有保守的TNF同源域，这一结构域使其能实现三聚化并与受体结合。同样存在膜结合型(mCD40L)和可溶性(sCD40L)两种形式，以非共价结合的同源三聚体发挥生物学活性。mCD40L可促进肿瘤消除，sCD40L则抑制免疫反应、阻碍细胞凋亡、促进肿瘤血管生成。此外，CD154还能与αIIbβ3、αMβ2、α5β1等多种整合素家族成员结合。表1 CD40/CD40L的结构及分类 3 CD40/CD40L的相互作用：CD40/CD40L的结合位点位于CD40L三聚体的亚基间凹槽，结合界面存在电荷互补，对下游信号传导至关重要。图2 CD40/CD40L检查点分子加工和相互作用 4 CD40/CD40L的氨基酸序列 Extracellular Helical Cytoplasmic 21-193 194-215 216-277 CD40:MVRLPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVCGPQDRLRALVVIPIIFGILFAILLVLVFIKKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ Extracellular Helical Cytoplasmic 47-261 23-46 1-22 CD40L:MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKIEDERNLHEDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETKKENSFEMQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL 2 仁域 CD40/CD40L的表达与调控 1 CD40的表达与调控：在免疫和非免疫细胞上均有表达，其表达受多种转录因子调控，在不同细胞中的表达各异，在B细胞和髓系细胞中CD40表达相对较高。“危险”信号（如病原体相关分子模式、损伤相关分子模式）及炎症细胞因子（如粒细胞/巨噬细胞集落刺激因子、白细胞介素-3和干扰素-γ等）等可提升mCD40的表达水平。 2 CD40L的表达与调控：CD40L在T细胞和血小板中表达较高。静息CD4⁺T细胞几乎检测不到mCD40L，而激活后的CD4⁺T细胞会高表达mCD40L，且其表达受多种机制严格调控。在血小板中，静息时无mCD40L表达，受到刺激后，mCD40L会快速且短暂地表达。此外，mCD40L在其他免疫细胞（如CD8⁺T细胞、肥大细胞、嗜碱性粒细胞等）以及条件先天免疫细胞（如内皮细胞、血管平滑肌细胞等）中也可诱导表达。图3 原代人细胞中的 CD40 和 CD40L 表达谱 3 CD40/CD40L的细胞内信号传导：CD40信号主要经通过招募肿瘤坏死因子受体相关因子(TRAF)家族成员以细胞类型和刺激依赖性方式介导，不同TRAF成员与CD40结合，激活不同信号通路。这些信号通路包括NF-κB、MAPK、PI3K/AKT、JAK3/STAT等，进而调节细胞的增殖、分化、凋亡等过程。图4 CD40/CD40L信号通路 3 仁域 CD40/CD40L相互作用的效应功能 1 对免疫细胞的作用：CD40在多种免疫细胞上表达，其激活对不同免疫细胞有不同影响。促进B细胞增殖、分化、产生抗体；激活髓系细胞，增强抗菌活性；促进树突细胞(DCs)的激活与成熟；调节T细胞分化、激活和记忆维持；促进血小板激活和聚集；促进巨噬细胞从M2型向M1型转化，分泌细胞因子；促进中性粒细胞的激活和脱颗粒。图5 CD40刺激对肿瘤微环境中免疫细胞的影响 2 CD40/CD40L的病理功能免疫调节作用：调节免疫反应和炎症，促进T细胞与B细胞相互作用，激活抗原呈递细胞，启动适应性免疫反应，影响肿瘤微环境和癌症进展。炎症反应中的作用：诱导促炎细胞因子生成，激活内皮细胞，促进白细胞募集和炎症驱动的血管生成，还可激活细胞内信号通路，促进抗肿瘤免疫反应。与肿瘤细胞的相互作用：激活抗原呈递细胞，增强肿瘤细胞MHC分子表达，促进免疫原性细胞死亡，增加肿瘤细胞对T细胞裂解的敏感性，调节肿瘤相关巨噬细胞表型，在不同癌症中发挥不同作用。此外，二者结合后可激活APC，促进生发中心形成、抗体类别转换等。图6 CD40/CD40L相互作用的效应功能 3 对肿瘤细胞的两面性：CD40/CD40L相互作用在肿瘤细胞中的作用具有两面性。一方面，在B细胞恶性肿瘤（如非霍奇金淋巴瘤、慢性淋巴细胞白血病、多发性骨髓瘤）中，它可促进肿瘤细胞增殖、抑制凋亡，上调促炎细胞因子和共刺激分子，增强T细胞启动；另一方面，它也能诱导某些肿瘤细胞（如恶性B细胞、乳腺癌、肾细胞癌等）生长停滞和凋亡，这主要取决于肿瘤细胞类型和免疫微环境。 4 仁域 CD40/CD40L靶向治疗图7 CD40/CD40L靶向治疗的策略和机制 1 激动剂疗法：主要用于肿瘤免疫治疗和疫苗佐剂。通过增强CD40/CD40L信号激活免疫细胞、诱导肿瘤细胞凋亡，已在多种恶性肿瘤早期临床试验中进行评估。在抗肿瘤治疗中疗效相对较低，完全缓解率为2%-20%，部分缓解率为4%-28.6%，且单药治疗效果不佳，存在剂量限制性副作用，如肝损伤、细胞因子释放综合征等。表2 CD40激动剂治疗的临床试验表3 CD40L激动剂治疗的临床试验 2 拮抗剂疗法：主要用于器官移植和自身免疫病治疗。阻断CD40/CD40L相互作用，抑制免疫细胞激活，用于治疗自身免疫性疾病和B细胞恶性肿瘤。在自身免疫性疾病治疗中，临床反应率为46%-75%，展现出一定的前景，阻断CD40/CD40L通路理论上可调节免疫反应，减少自身抗体产生和组织损伤。但在临床试验中，第一代药物出现了血栓栓塞或免疫抑制等严重副作用，第二代药物安全性有所提升。表4 CD40拮抗剂治疗的临床试验表5 CD40L拮抗剂治疗的临床试验 3 双特异性CD40抗体 ①靶向肿瘤相关抗原(TAA)的双抗可增强疗效并实现安全给药。 ②靶向CD47的双抗能阻断“别吃我”信号，增强抗肿瘤效果。 ③靶向PD-L1的双抗因CD40结合导致的短半衰期，在维持PD-L1受体持续占位上存在挑战。 ④靶向肿瘤基质蛋白的双抗可定向激活TME中的免疫细胞，但无法像TAA靶向双抗那样促进肿瘤特异性T细胞的交叉启动。 ⑤靶向T细胞受体的双抗能重新激活肿瘤特异性T细胞，部分药物已进入临床试验阶段。图8 基于第二个靶点性质的不同类别的双特异性CD40抗体 4 其他CD40靶向方式：CD40靶向疫苗可增强抗原呈递，激发T细胞反应，部分处于研发阶段；CD40靶向纳米颗粒能改善癌症疫苗递送和疗效；基于基因疗法的CD40刺激，使用不同病毒递送系统，在临床前和临床试验中均展现出一定潜力。表6 基于CD40配体的新兴靶向疗法临床试验总结 5 联合治疗：目前CD40/CD40L靶向治疗临床效果有限，联合免疫刺激疗法可增强抗肿瘤反应。联合化疗可增加肿瘤抗原的可用性，联合ICI可增强肿瘤特异性T细胞的活性和功能，联合TLR激动剂可增强T细胞反应，还可与抗血管生成治疗等联合。在临床应用中，针对不同类型的肿瘤，如非炎症性肿瘤（如胰腺癌、结直肠癌）可联合化疗，炎症性肿瘤（如膀胱癌）可联合ICI，以提高治疗效果。表7 CD40-CD40L 靶向治疗的临床疗效总结 5 仁域 CD40/CD40L与自身免疫性疾病系统性红斑狼疮(SLE)：SLE患者的CD40/CD40L表达均上调，血清中sCD40L水平也增加。在SLE的发病过程中，CD40L在Tfh细胞上表达，驱动生发中心内B细胞的异常活化和分化，产生大量自身抗体，可促进免疫细胞间的相互作用，增强炎症反应，引发组织损伤，与疾病的进展密切相关。此外，CD40L还可与整合素家族受体结合，促进炎症因子释放，增强血小板活化和聚集，影响SLE的发病和进展。阻断CD40/CD40L通路可降低抗双链DNA抗体滴度，改善疾病相关指标。图9 CD40/CD40L在SLE发病机制中相互作用的模型类风湿关节炎(RA)：在RA患者中，CD40和CD40L的表达均上调，CD40L在T细胞上的过表达与疾病活动度相关，高水平表达往往伴随着更高的疾病活动和更少的缓解。CD40通路不仅参与了RA患者体内类风湿因子等自身抗体的产生，还直接影响滑膜成纤维细胞的功能。当滑膜成纤维细胞上的CD40与CD40L结合后，会促使细胞产生TNF、IL-1β和MMPs等炎症介质，进一步加剧炎症反应和关节破坏。银屑病关节炎(PsA)：PsA患者的CD40L表达增加。CD40/CD40L信号通路的异常激活，促进了免疫细胞的活化和炎症细胞因子的分泌，如IL-17、IL-23等，参与皮肤和关节的炎症反应，导致皮肤病变和关节损伤。在皮肤病变中，CD40/CD40L信号通路可能通过影响角质形成细胞的增殖和分化、炎症细胞的浸润，并参与银屑病的发病过程。在关节部位，CD40/CD40L信号通路还可促进滑膜细胞的炎症反应和骨侵蚀。强直性脊柱炎(AS)：在AS患者中，CD40/CD40L信号通路也参与了疾病的发生发展。CD40L在T细胞、单核细胞等免疫细胞上表达上调，与CD40结合后，激活下游信号通路，促进炎症细胞因子的分泌，可引起脊柱关节和骶髂关节的炎症反应，导致关节疼痛、僵硬和骨质破坏。此外，CD40/CD40L信号通路还可能影响成骨细胞和破骨细胞的功能，打破骨代谢平衡，导致新骨形成和骨赘形成，最终引起脊柱强直和关节畸形。干燥综合征(Sjögren'ssyndrome)：CD40/CD40L相互作用会诱导细胞表达黏附分子如ICAM-1，促进炎症细胞的浸润和组织损伤。在小鼠模型中，阻断CD40/CD40L通路可预防干燥综合征的发生发展，表明该通路在疾病进程中起着重要作用。自身免疫性肾炎(如FSGS)：在局灶节段性肾小球硬化(FSGS)中，正常情况下肾脏不表达CD40，但患者的肾小球足细胞会异常表达CD40，且可被CD40L进一步诱导。可能导致足细胞功能受损，如改变细胞的肌动蛋白细胞骨架，增加肾小球的通透性，进而引发蛋白尿和肾脏损伤。炎症性肠病(IBD)：包括克罗恩病(CD)和溃疡性结肠炎(UC)。在IBD患者中，CD40L和CD40在循环系统和肠道黏膜中均高表达。CD40/CD40L相互作用可诱导肠道微血管内皮细胞产生趋化因子和细胞因子，促进炎症细胞浸润，破坏肠道屏障功能，与疾病的病理生理过程直接相关。自身免疫性皮肤疾病(如系统性硬化症SSc和SLE皮肤病变)：在系统性硬化症中，皮肤成纤维细胞的CD40表达显著上调，与CD40L结合后，会促使成纤维细胞产生IL-6、IL-8等促炎细胞因子和趋化因子，还可诱导CD80表达，加剧炎症反应。同时，CD40L在血液T细胞和皮肤病变部位也高表达，sCD40L与疾病的血管并发症和自身抗体产生相关。在SLE皮肤病变中，也存在CD40/CD40L通路的异常激活。 1型糖尿病(T1D)：人类胰腺导管细胞和胰岛β细胞均表达CD40，与CD40L结合后会产生促炎细胞因子，可能参与T1D的发病过程以及胰岛移植后的排斥反应。T1D患者体内sCD40L水平和血小板表面CD40L表达均显著升高，为CD40的激活提供了更多来源。多发性硬化症(MS)：MS患者血清中sCD40L水平与血脑屏障破坏的指标存在相关性，B细胞可通过CD40途径被激活，增强CD8+T细胞的颗粒酶B分泌。但也有研究表明MS患者血清中sCD40L水平降低，且CD40基因的一个等位基因及其mRNA表达降低与MS发病风险相关，说明该通路在MS中的作用较为复杂。 6 仁域 CD40/CD40L与神经系统疾病创伤性脑损伤：CD40和CD40L在创伤部位的巨噬细胞和小胶质细胞上表达，血清sCD40L水平与TBI严重程度及30天死亡率正相关，降低CD40表达可减轻脑水肿。阿尔茨海默病：CD40L刺激小胶质细胞干扰APP处理和tau磷酸化，导致神经纤维缠结和β-淀粉样斑块形成，其在淀粉样斑块周围的星形胶质细胞中有强烈免疫反应。帕金森病：CD40刺激小胶质细胞和星形胶质细胞后，上调的诱导型一氧化氮合酶和环氧化酶-2可能导致多巴胺能神经元选择性丢失。缺血性中风：CD40L在动脉粥样硬化相关细胞中表达，可降低斑块稳定性。在动物模型中，CD40和CD40L缺陷小鼠的梗死体积减小。癫痫：在中风后癫痫患者中，血浆sCD40L水平和白细胞中CD40表达显著升高，下调CD40-CD40L可减轻动物模型的癫痫易感性和严重程度。神经损伤：在脊髓损伤动物模型中，CD40+小胶质细胞增加，促进CD40L+T细胞浸润和细胞因子介导的损伤，还会通过多种机制导致神经性疼痛。多发性硬化：患者的脱髓鞘斑块中，T细胞和小胶质细胞分别表达CD40L和CD40，相互作用后释放多种物质增加脱髓鞘，CD40表达的B细胞也参与其中，同时该信号与血脑屏障破坏有关。肌萎缩侧索硬化：约56%患者血液中CD40信号上调，针对CD40L的单克隆抗体可延缓小鼠瘫痪并延长生存期。重症肌无力：CD40L基因敲除小鼠对MG诱导完全抵抗，失调的CD40信号会破坏免疫耐受。脑肿瘤：在胶质瘤中，CD40/CD40L的表达与预后相关，激动剂可增强肿瘤内T细胞反应，但也会导致肿瘤侵袭性、克隆性和耐药性增加，还会促进肿瘤血管生成。图10 CD40/CD40L对神经病学的影响 7 仁域 CD40/CD40L与心血管疾病动脉粥样硬化：CD40/CD40L广泛表达于动脉粥样硬化病变处的多种免疫和非免疫细胞上，促进炎症细胞因子分泌、细胞黏附分子表达以及细胞间的相互作用，影响脂质代谢和斑块稳定性；同时，CD40基因的单核苷酸多态性与动脉粥样硬化易感性相关，而可溶性CD40L对动脉粥样硬化的影响存在争议，整体上抑制CD40-CD40L系统虽可能预防动脉粥样硬化，但长期抑制会带来免疫抑制等问题。图11 动脉粥样硬化中的CD40/CD40L相互作用 8 仁域 CD40/CD40L与恶性肿瘤分析TCGA数据库发现，CD40在黑色素瘤、肾细胞癌和胰腺癌中均有表达，且与多种免疫相关基因存在相关性，这些基因涉及抗原呈递、T细胞功能等。表8 CD40L对不同类型癌症的影响抗体发现服务 & 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。可为客户提供14天、100%成功率的先导抗体分子发现服务，彻底解决传统抗体定制的周期长、失败率高、成本高三大难题。目前已经成功完成300+靶点抗体筛选项目！ 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，持续更新相关内容参考文献 Fatima T, Mirza A, Fatima F, Karamat RI, Ahmad B, Naeem S, Shahid I, Akilimali A. Frexalimab (SAR441344) as a potential multiautoimmune disorder tackling mAB targeting the CD40-CD40L pathway undergoing clinical trials: a review. Ann Med Surg (Lond). 2024 Nov 12;86(12):7305-7313. Allard CC, Salti S, Mourad W, Hassan GS. Implications of CD154 and Its Receptors in the Pathogenesis and Treatment of Systemic Lupus Erythematosus. Cells. 2024 Sep 28;13(19):1621. Pazoki A, Dadfar S, Shadab A, Haghmorad D, Oksenych V. Soluble CD40 Ligand as a Promising Biomarker in Cancer Diagnosis. Cells. 2024 Jul 28;13(15):1267. Andersson H, Nyesiga B, Hermodsson T, Enell Smith K, Hägerbrand K, Lindstedt M, Ellmark P. Next-generation CD40 agonists for cancer immunotherapy. Expert Opin Biol Ther. 2024 May;24(5):351-363. Tian S, Wang Y, Wan J, Yang M, Fu Z. Co-stimulators CD40-CD40L, a potential immune-therapy target for atherosclerosis: A review. Medicine (Baltimore). 2024 Apr 5;103(14):e37718. Zhou Y, Richmond A, Yan C. Harnessing the potential of CD40 agonism in cancer therapy. Cytokine Growth Factor Rev. 2024 Feb;75:40-56. Lang I, Zaitseva O, Wajant H. FcγRs and Their Relevance for the Activity of Anti-CD40 Antibodies. Int J Mol Sci. 2022 Oct 25;23(21):12869. Strohm L, Ubbens H, Münzel T, Daiber A, Daub S. Role of CD40(L)-TRAF signaling in inflammation and resolution-a double-edged sword. Front Pharmacol. 2022 Oct 4;13:995061. Ots HD, Tracz JA, Vinokuroff KE, Musto AE. CD40-CD40L in Neurological Disease. Int J Mol Sci. 2022 Apr 8;23(8):4115. Bullock TNJ. CD40 stimulation as a molecular adjuvant for cancer vaccines and other immunotherapies. Cell Mol Immunol. 2022 Jan;19(1):14-22. Bosmans LA, Bosch L, Kusters PJH, Lutgens E, Seijkens TTP. The CD40-CD40L Dyad as Immunotherapeutic Target in Cardiovascular Disease. J Cardiovasc Transl Res. 2021 Feb;14(1):13-22. Enell Smith K, Deronic A, Hägerbrand K, Norlén P, Ellmark P. Rationale and clinical development of CD40 agonistic antibodies for cancer immunotherapy. Expert Opin Biol Ther. 2021 Dec;21(12):1635-1646. Tang T, Cheng X, Truong B, Sun L, Yang X, Wang H. Molecular basis and therapeutic implications of CD40/CD40L immune checkpoint. Pharmacol Ther. 2021 Mar;219:107709. Li DK, Wang W. Characteristics and clinical trial results of agonistic anti-CD40 antibodies in the treatment of malignancies. Oncol Lett. 2020 Nov;20(5):176. Zhang S, Breidenbach JD, Russell BH, George J, Haller ST. CD40/CD40L Signaling as a Promising Therapeutic Target for the Treatment of Renal Disease. J Clin Med. 2020 Nov 13;9(11):3653. Vonderheide RH. CD40 Agonist Antibodies in Cancer Immunotherapy. Annu Rev Med. 2020 Jan 27;71:47-58. Lai JH, Luo SF, Ho LJ. Targeting the CD40-CD154 Signaling Pathway for Treatment of Autoimmune Arthritis. Cells. 2019 Aug 18;8(8):927. Karnell JL, Rieder SA, Ettinger R, Kolbeck R. Targeting the CD40-CD40L pathway in autoimmune diseases: Humoral immunity and beyond. Adv Drug Deliv Rev. 2019 Feb 15;141:92-103.

临床1期临床终止

2025-02-12

·Endpoints

Biogen gets $250M in Royalty Pharma deal for Phase 3 lupus program

Biogen is turning to Royalty Pharma for some cash in exchange for rights to a lupus program, the companies announced Wednesday. The two have agreed on a deal for litifilimab, an anti-BDCA2 drug currently in Phase 3 trials for two kinds of lupus. Biogen will get $250 million in cash, which it will use to continue developing the program, while Royalty Pharma may get undisclosed payments based on regulatory milestones, as well as royalty payments in the mid-single digits. The announcement coincided with Biogen’s fourth-quarter earnings, in which Biogen beat Wall Street expectations for earnings per share, as well as sales of the Alzheimer’s drug Leqembi. Biogen investors have begun growing restless , as the company looks for ways to create long-term growth. CEO Chris Viehbacher and other executives have previously said the company has between $5 billion and $10 billion to make an acquisition before the end of the year. During last quarter’s call with analysts, Viehbacher faced questions about Biogen’s lupus efforts, with some wondering why the company wasn’t focusing on bringing CAR-T to lupus like many other biopharmas. In addition to litifilimab, Biogen also has an anti-CD40 program in Phase 3 testing for lupus called dapirolizumab pegol, which succeeded in one Phase 3 study last year and has a second trial that has launched. Biogen also noted that it’s completed $400 million in net savings of its cost-cutting program announced in mid-2023. The goal of $1 billion in gross savings is still on track to wrap up by the end of 2025. (Last month’s research reorganization is not part of these cuts.) In addition, Biogen announced that it is trimming four programs from its early-stage pipeline: BIIB113, an oral inhibitor of tau aggregation for Alzheimer’s disease; BIIB094, an antisense oligonucleotide targeting LRRK2 for Parkinson’s disease; BIIB101, an Ionis-partnered antisense drug for multiple system atrophy; and BIIB143/cemdomespib, a drug from Reata in diabetic neuropathic pain.

寡核苷酸临床3期

2025-01-15

·BioSpace

Under Pressure to Deal, Biogen Executives Deflect Urgency at JPM25

iStock, Agustin Vai While investors and analysts push for a deal, Biogen CEO Chris Viehbacher and Head of Development Priya Singhal refuse to make one out of desperation. Biogen’s Head of Development Priya Singhal, and CEO Chris Viehbacher for that matter, are well aware of the pressure from investors. The company’s shares have fallen to a five-year low of $143. Investors are repeatedly asking when they might strike another deal. “The stock price is down, but we are trying to focus on, how do we continue to show the momentum and the growth? Because I think people didn’t believe us on a lot of the things, but we were able to kind of bring the proof forward,” Singhal told BioSpace in an interview on the sidelines of the J.P. Morgan Healthcare Conference. “Hopefully the stock price will follow. We’re trying to focus on what we can control, which is growth and scientific conviction in the pipeline.” Investors have always underestimated Biogen’s ability to follow through on lofty goals, from getting an Alzheimer’s drug approved to now filing a request to clear a subcutaneous version in an attempt to ease the administration burden, Singhal said. But they did that on Monday, proving again that they can execute. “I can understand it, because in the past, there were [proof of concept] failures, but now I think the proof’s in the pudding,” Singhal said. “And in 2024 I think we’ve been able to show the proof, and we have set it up for successive positive readouts potentially.” A major milestone in 2024 was the positive readout for dapirolizumab pegol (dapi), which had previously failed a Phase II test in 2018. The Phase III PHOENYCS GO trial met its primary endpoint with a 49.5% response rate among patients with systemic lupus erythematosus, clearing a path for a regulatory filing. This compared to 34.6% in those who received just standard of care. “I can tell you that before dapi read out positive, there wasn’t a lot of excitement about dapi. But now the equation’s changed,” Singhal said. Other milestones were data for high-dose Spinraza in spinal muscular atrophy, global approvals for Friedreich’s ataxia treatment Skyclaris and enrollment for the tau-targeting Alzheimer’s treatment BIIB080 in a Phase II trial. Biogen also bought Human Immunology Biosciences last year for $1.15 billion upfront, at least momentarily silencing the constant drum beat of analysts and investors asking for a deal. But of course heading into J.P. Morgan that call had picked up again. Biogen did announce a potential deal, an unsolicited bid for partner Sage Therapeutics. Singhal could not talk about the deal, only saying that they were required to disclose the offer under SEC rules. In his J.P. Morgan presentation, Viehbacher stressed that Biogen is not desperate for deals. “I see some proposals that we should be prepared to overpay. We’re never going to do that, not knowingly anyway. So I think that’s where the discipline of capital is,” he said during the Tuesday fireside chat. Biogen is facing some tough changes with the multiple sclerosis franchise declining, which was pointed out in a note from BMO Capital Markets. “While we agree with Mr. Viehbacher’s strategy, we expect limited acquisition opportunities will make it increasingly challenging to patch the hole that continues to widen with MS franchise erosion,” BMO’s Evan Seigerman wrote. “Business development continues to be needed, but limited revenue-generating opportunities at a reasonable price continue to box Biogen in to investing in early-stage assets.” Singhal agreed that the MS business is declining, but said it’s taking “more of a glide.” Viehbacher said another company like Reata Pharmaceuticals, which brought with it Skyclarys, would be a perfect match. Singhal underscored an all of the above approach that spans early science to early stage revenue-generating assets. She said Biogen has outlined most importantly what it won’t do, which includes oncology and “big immunology” diseases like rheumatoid arthritis or psoriasis. Instead, the company will stick to specialty immunology, rare diseasesand of course neuroscience. “The Reatas and HiBios of the world are hard to find, so we’re being very purposeful about how we’re looking,” Singhal said. Singhal too, deflected the urgency to conduct a deal. “There’s the sentiment that we have to do a deal, and I think what I want to clarify is that that’s just our everyday business. We’re always looking at internal and external innovation. But do we believe that a deal at any cost is critical to drive Biogen growth? That’s not the case, because we believe that we are really positioned very well.”

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适应症	最高研发状态	国家/地区	公司	日期
系统性红斑狼疮	临床3期	美国	UCB Biopharma SRL	2020-08-12
系统性红斑狼疮	临床3期	阿根廷	UCB Biopharma SRL	2020-08-12
系统性红斑狼疮	临床3期	澳大利亚	UCB Biopharma SRL	2020-08-12
系统性红斑狼疮	临床3期	奥地利	UCB Biopharma SRL	2020-08-12
系统性红斑狼疮	临床3期	比利时	UCB Biopharma SRL	2020-08-12
系统性红斑狼疮	临床3期	保加利亚	UCB Biopharma SRL	2020-08-12
系统性红斑狼疮	临床3期	加拿大	UCB Biopharma SRL	2020-08-12
系统性红斑狼疮	临床3期	智利	UCB Biopharma SRL	2020-08-12
系统性红斑狼疮	临床3期	哥伦比亚	UCB Biopharma SRL	2020-08-12
系统性红斑狼疮	临床3期	捷克	UCB Biopharma SRL	2020-08-12

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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


NCT04294667 (PHOENYCS GO, ACR2024) 人工标引	临床3期	系统性红斑狼疮	315	Dapirolizumab pegol + SOC	憲鏇衊餘窪淵廠餘夢鏇(鏇蓋鏇蓋壓憲鹹廠選鹹) = 網願憲積鏇夢積壓簾艱膚廠淵艱淵製憲積壓鏇 (膚襯糧構窪構觸衊衊鑰 ) 达到更多	积极	2024-10-24
				Placebo+SOC	憲鏇衊餘窪淵廠餘夢鏇(鏇蓋鏇蓋壓憲鹹廠選鹹) = 壓齋膚餘簾選鹽鹽廠觸膚廠淵艱淵製憲積壓鏇 (膚襯糧構窪構觸衊衊鑰 ) 达到更多
NCT04294667 (PHOENYCS GO, NEWS) 人工标引	临床3期	系统性红斑狼疮	321	dapirolizumab pegol	餘壓鹽鹹築窪齋觸繭鏇(壓網網膚鹹遞製網壓鏇) = The trial achieved its primary endpoint. 鹹壓積夢夢簾壓繭遞簾 (齋襯鬱簾選遞艱鏇膚鹽 ) 达到更多	积极	2024-09-24
NCT02804763 (Pubmed) 人工标引	临床2期	系统性红斑狼疮	-	PBO+SOC	窪壓獵醖蓋鬱鏇積壓積(窪範夢糧觸衊鏇蓋獵蓋) = 積簾鏇選簾憲築鑰鬱壓醖廠齋壓鬱繭衊繭範鹽 (範醖淵願憲積製鬱夢憲 ) 未达到更多	不佳	2021-11-03
				dapirolizumab pegol 6 mg/kg+SOC	窪壓獵醖蓋鬱鏇積壓積(窪範夢糧觸衊鏇蓋獵蓋) = 鹽鑰鹽鹹獵憲憲鏇醖顧醖廠齋壓鬱繭衊繭範鹽 (範醖淵願憲積製鬱夢憲 ) 未达到更多
NCT01764594 (Pubmed \| Arthritis Rheumatol) 人工标引	临床1期	系统性红斑狼疮	24	dapirolizumab pegol	遞築鏇鹹觸鏇齋積鏇夢(積築範遞齋願壓積鬱獵) = 積鏇壓膚蓋構鏇衊窪餘淵鹽餘選蓋衊膚鬱齋鑰 (鹹鏇簾醖選鹹餘壓艱蓋 ) 更多	积极	2017-11-01
				Placebo	遞築鏇鹹觸鏇齋積鏇夢(襯壓廠繭簾網餘齋廠壓) = 膚膚獵餘觸窪膚顧製艱夢積鬱廠鑰夢築繭製餘 (遞築範簾壓膚築淵範憲 ) 更多
NCT01764594 (Pubmed \| Ann Rheum Dis)	临床1期	系统性红斑狼疮 antidouble stranded DNA \| antinuclear antibodies	-	Dapirolizumab pegol 30 mg/kg followed by 15 mg/kg every 2 weeks	鹹廠夢淵簾鑰積鑰觸餘(選齋衊襯鹹鬱壓鬱壓製) = 鹽壓鹽齋繭鏇鏇製選選廠夢鏇廠醖製顧衊觸鏇 (遞選糧淵範憲築衊憲繭 )	积极	2017-11-01
				Placebo regimen	鹹廠夢淵簾鑰積鑰觸餘(選齋衊襯鹹鬱壓鬱壓製) = 鏇糧繭範網壓鏇廠艱簾廠夢鏇廠醖製顧衊觸鏇 (遞選糧淵範憲築衊憲繭 )
NCT01093911 (Pubmed) 人工标引	临床1期	系统性红斑狼疮	28	CDP7657 (healthy individuals)	鏇齋憲餘夢鏇糧獵鏇窪(鏇襯網壓遞蓋鹽遞蓋遞) = 願夢蓋憲壓構窪醖廠鹹艱襯積製窪鹹網願鹽夢 (築夢膚願壓醖範憲鬱遞 )	积极	2015-03-16
				Placebo (healthy individuals)	-