预约演示
更新于：2025-10-04
Cycloserine
环丝氨酸
更新于：2025-10-04
概要
基本信息
原研机构 |
最高研发阶段批准上市 |
首次获批日期 美国 (1964-06-29), |
最高研发阶段(中国)批准上市 |
特殊审评特殊审批 (中国) |
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结构/序列
分子式C3H6N2O2 |
InChIKeyDYDCUQKUCUHJBH-UWTATZPHSA-N |
CAS号68-41-7 |
关联
163
项与 环丝氨酸 相关的临床试验CTR20250638
环丝氨酸胶囊在健康受试者中空腹给药条件下随机、开放、单剂量、两制剂、两序列、两周期、双交叉生物等效性试验
主要目的：考察中国健康受试者在空腹条件下单次口服由浙江众延医药科技有限公司持有，浙江赛默制药有限公司生产的环丝氨酸胶囊（规格：250mg）与Meiji Seika ファルマ株式会社持证的环丝氨酸胶囊（规格：250mg）后的体内药代动力学特征，评价两制剂的生物等效性。
次要目的：评价单剂量口服环丝氨酸胶囊受试制剂及参比制剂在中国健康受试者中的安全性。
开始日期2025-04-02 |
申办/合作机构 |
ChiCTR2500097631
An exploratory trial of safety and efficacy of D-cycloserine in the treatment of amyotrophic lateral sclerosis (ALS)
开始日期2025-02-28 |
申办/合作机构- |
ChiCTR2500095767
Clinical efficacy of NMDA receptor glycine binding site-targeted drugs to enhance the antidepressant efficacy of iTBS
开始日期2024-10-18 |
申办/合作机构- |
100 项与 环丝氨酸 相关的临床结果
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100 项与 环丝氨酸 相关的转化医学
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100 项与 环丝氨酸 相关的专利（医药）
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4,000
项与 环丝氨酸 相关的文献（医药）2025-12-01·Natural Products and Bioprospecting
Harnessing Actinobacteria secondary metabolites for tuberculosis drug discovery: Historical trends, current status and future outlooks
Review
作者: de Souza, Thalisson Amorim ; de Oliveira, Genil Dantas ; de Almeida, Luana Layse Câmara ; Cibulski, Samuel Paulo ; Rodrigues-Junior, Valnês S ; Fernandes, Sayoane Pessoa ; da Silveira Silva, Marcelly
Abstract:
Tuberculosis (TB) is a leading infectious disease killer and one of the major causes of deaths worldwide. Although TB is a curable and preventable disease, in 2023, approximately 10.8 million people fell ill with TB and there were an estimated 1.25 million of deaths worldwide. Despite some research progress for new drug candidates, drug repurposing, and new regimens, there is still an urgent need for the new medicins to treat TB, especially due to the growing cases of multidrug and extensively drug-resistant (MDR/XDR) strains. Drug resistance is a challenging obstacle to TB care and prevention globally, making TB harder and longer to treat, often with poorer outcomes for patients. The Actinomycetota encompass Gram-positive bacteria that produce a milieu of bioactive metabolites, including antibiotics, antiproliferative drugs, immunosuppressive agents, and other important medical molecules. Actinomycetota have a special place in the therapeutic arsenal to fight TB, as rifamycins, aminoglycosides, and cycloserine are derived from Streptomyces species, one of the most important genera in this phylum. Furthermore, hundreds of antimycobacterial metabolites have been isolated from Actinomycetota and can serve as effective drugs or useful agents for the discovery of new lead compounds to combat TB. The present review covers more than 171 isolated substances as potential antimycobacterial agents discovered between the years 1972 to 2024. Among the most potent compounds, with MIC in the submicromolar range, steffimycins, ilamycins/rufomycins, nosiheptide, actinomycins, lassomycin and boromycin are the most promising compounds. These compounds represent highly promising candidates for development of new antitubercular drugs. Additionally, some of these substances also demonstrated activity against resistant Mycobacterium tuberculosis (Mtb) strains, which is particularly relevant given the difficulty of treating MDR and XDR strains. Thus, actinobacteria have played and continue to play an important role in fight TB, remaining a promising source of antibiotic metabolites. Their unique metabolic diversity enables the production of metabolites with innovative mechanisms of action, making them a strategic reservoir for discovering therapies against untreatable forms of the disease.Graphical Abstract
2025-10-01·INTERNATIONAL IMMUNOPHARMACOLOGY
Therapeutic effects of D-cycloserine in mouse models of IBD and CAC: Targeting NLRP3 inflammasome and intestinal barrier integrity
Article
作者: Chen, Fengying ; Ju, Xianghong ; Zhuang, Jionghan ; Meng, Wei ; Yang, Shihua ; Abd El-Aty, A M ; Guo, Yonglong ; Chen, Shengwei ; Zeng, Jingtao ; Yan, Lizhuowen
D-Cycloserine (DCS), a broad-spectrum antibiotic and NMDA receptor modulator, exhibits immunomodulatory effects beyond its known neurological and antimicrobial functions. This study investigated DCS's therapeutic potential in inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC) using in vitro and in vivo models. In lipopolysaccharide (LPS)-stimulated NCM460 cells, DCS inhibited NLRP3 inflammasome activation and restored tight junction protein expression. In dextran sulfate sodium (DSS)-induced murine colitis, both preventive and therapeutic DCS regimens attenuated inflammation, reduced histopathological damage, and preserved intestinal barrier integrity. In azoxymethane (AOM)/DSS-induced CAC, DCS decreased tumor burden and reduced Ki-67+ cell proliferation without systemic toxicity. These findings position DCS as a promising dual-target candidate for IBD and CAC management through NLRP3-caspase-1-GSDMD pathway inhibition and epithelial barrier maintenance.
2025-10-01·NEUROSCIENCE
Sequential administration of D-cycloserine and MK801 reduces pERK-expressing neurons in the lateral amygdala and disrupts threat memory reconsolidation
Article
作者: Johnson, Luke R ; Canales, Juan J ; Sohal, Sukhwinder S ; Caruso, Vanni ; Ahamed, Sayed K ; James, Fionnghuala ; Raut, Sanket B
Post-traumatic stress disorder (PTSD) is characterized by persistent threat-related memories for which there are limited effective treatment options. The N-methyl-D-aspartate (NMDA) receptor-dependent extracellular signal-regulated kinase (ERK) pathway in the lateral amygdala (LA) is necessary for synaptic plasticity, threat memory consolidation and reconsolidation. Disruption of these memories during the reconsolidation window has been proposed as a therapeutic strategy for PTSD, however, no current therapies using this strategy are available. To disrupt reconsolidation, memories must first be brought into a labile state. We investigated the effect of the NMDA receptor partial agonist D-cycloserine (DCS) and the ketamine-like non-competitive antagonist MK801 on threat memory reconsolidation in mice. Using auditory threat conditioning, DCS, or saline vehicle, was administered one hour before memory reactivation to facilitate labilization of a recalled threat memory, followed by MK801 or a saline vehicle after reactivation. Experimental groups included vehicle, DCS 15 mg/kg, MK801 0.06 mg/kg, and MK801 0.12 mg/kg alone and in combination. The effect of behavioural and drug interventions on phospho-ERK-expressing neurons in the LA was analysed using neuron counting and topographical mapping in the LA. MK801 alone and in combination with DCS reduced the number of pERK neurons in the LA across all doses. Freezing behaviour was reduced by high-dose MK801 when combined with DCS. These findings suggest that DCS and MK801 together effectively disrupt threat memory reconsolidation in the LA and offer an NMDA-based combined drug and behavioural treatment strategy for PTSD.
131
项与 环丝氨酸 相关的新闻（医药）2025-09-29
KETAFREE™ to provide innovative, preservative-free IV ketamine formulation, eliminating toxic preservatives, in keeping with current HHS priorities to eliminate toxic preservatives from foods and drugsFiling is based on FDA interaction and approval of Suitability Petition for NRx’s proposed strength of preservative-free ketamineThis presentation of ketamine represents a reshoring of a strategically important drug to the US, in keeping with the Presidential Executive Order signed on May 5, 2025. Ketamine faces a current US drug shortage not expected to abate in the near future1Current ketamine market estimated at $750 million and projected to reach $3.35 billion globally in 2034.2 NRx anticipates marketing KETAFREE™ for currently approved ketamine indicationsThe Company has filed a citizen’s petition with the FDA to remove benzethonium chloride, a known neurotoxic and cytotoxic substance, from all presentations of ketamine intended for intravenous useThis formulation of ketamine is distinct from the formulation used in the ongoing NDA submission for NRX-100 in suicidal ideation in depressed patients, including bipolar depression, which was recently granted Fast Track designation by the FDA WILMINGTON, Del., Sept. 29, 2025 (GLOBE NEWSWIRE) -- NRx Pharmaceuticals, Inc. (Nasdaq: NRXP), a clinical-stage biopharmaceutical company, today announced the re-filing of its Abbreviated New Drug Application (ANDA) to the U.S. Food and Drug Administration (FDA) for KETAFREE™, its preservative-free IV ketamine formulation, for use in all existing approved indications. The filing follows FDA grant of approval of its Suitability Petition for NRx’s proposed strength of preservative-free ketamine. The current annual ketamine market is estimated at $750 million, with global demand for ketamine projected to grow to $3.35 billion by 2034. This does not include the widespread use of compounded ketamine by clinics unable to obtain manufactured drug. NRx aims to capture a significant share of the current market. According to a 2021 survey, an estimated 5.1 million Americans had received ketamine for medical uses in their lifetime3, a number that continues to grow with increased clinical focus on this important medication. Ketamine currently faces a severe drug shortage according to the American Society of Hospital Pharmacists. Accordingly, NRx is seeking priority review from FDA. The Company previously filed a citizen’s petition with the FDA to remove benzethonium chloride (BZT), a known neurotoxic and cytotoxic substance, from presentations of ketamine intended for intravenous use. The FDA has previously disallowed the use of BZT in hand cleansers and topical antiseptics. A related preservative, benzalkonium chloride has demonstrated corneal and conjunctival toxicity in artificial tears and glaucoma medications, leading to use of preservative-free alternatives. NRx has filed expert testimony from accredited toxicologists regarding the toxicity of BZT, which is not generally recognized as safe (GRAS) by the FDA. Removal of potentially harmful preservatives from foods is a stated priority in the MAHA report and HHS leadership has additionally targeted preservatives in vaccines. BZT was originally added to ketamine when it was first formulated in the 1970s to maintain stability and sterility using the container closure systems then available. NRx has demonstrated long term stability and sterility with a patented preservative-free formulation using modern manufacturing methods. Return of strategic drugs to US manufacture (Reshoring) is a current US priority as stated in a Presidential executive order issued on May 5, 2025. This initiative particularly applies to drugs that are critical for inpatient care, such as ketamine. The NRx product is manufactured in partnership with Nephron Pharmaceuticals of West Columbia, SC. The formulation filed under the ANDA is distinct from that used in the New Drug Application (NDA), for which the Company has received Fast Track Designation for Treatment of Suicidal Ideation in Depression, including Bipolar Depression. The Company anticipates submitting clinical trial data from more than 1,000 patients and real-world data from more than 180,000 patients in which ketamine demonstrated superiority to placebo and active placebo, with noninferiority to electroconvulsive therapy. Should both the ANDA and the NDA be approved, the resulting commercial products would have different, non-substitutable product numbers and different commercial paths. “We appreciate FDA’s rapid response to our suitability petition and look forward to advancing our preservative-free ketamine presentation to market,” said Jonathan Javitt, MD, MPH, Chairman and CEO of NRx Pharmaceuticals. “KETAFREE™ is designed to replace older formulations that rely on potentially neurotoxic and cytotoxic preservatives for stability and sterility, and to reshore the manufacture of a strategically-important drug to the US. We have filed a US patent on our novel, preservative-free formulation, which anticipates three years of room-temperature shelf stability.” About NRx Pharmaceuticals, Inc. NRx Pharmaceuticals, Inc. (www.nrxpharma.com), is a clinical-stage biopharmaceutical company developing therapeutics based on its NMDA platform for the treatment of central nervous system disorders, specifically suicidal depression, chronic pain, and PTSD. The Company is developing NRX-100 (preservative-free intravenous ketamine) and NRX-101 (oral D-cycloserine/lurasidone). NRX-100 has been awarded Fast Track Designation for the treatment of Suicidal ideation in Depression, including Bipolar Depression. NRX-101 has been awarded Breakthrough Therapy Designation for the treatment of suicidal bipolar depression. NRx has recently had a Suitability Petition granted, allowing re-filing of an Abbreviated New Drug Application (ANDA), and initiated a New Drug Application filing for NRX-100 with an application for the Commissioner’s National Priority Voucher Program for the treatment of suicidal depression. About HOPE Therapeutics, Inc. HOPE Therapeutics, Inc. (www.hopetherapeutics.com), a subsidiary of NRx Pharmaceuticals, is a Healthcare delivery company that is building a best-in-class network of interventional psychiatry clinics to offer ketamine, transcranial magnetics stimulation (TMS), and other lifesaving therapies to patients with suicidal depression and related disorders, together with a digital therapeutic-enabled platform designed to augment and preserve the clinical benefit of NMDA-targeted drug therapy. Notice Regarding Forward-Looking Statements The information contained herein includes forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, and Section 27A of the Securities Act of 1933, as amended. Forward-looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, and include words such as "may," "will," "should," "would," "expect," "plan," "believe," "intend," "look forward," and other similar expressions among others. These statements relate to future events or to the Company's future financial performance, and involve known and unknown risks, uncertainties and other factors that may cause the Company's actual results to be materially different from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. The Company has reported regulatory milestones as they have been achieved but has not predicted the outcome of any future regulatory determination. You should not place undue reliance on forward-looking statements since they involve known and unknown risks, uncertainties and other factors which are, in some cases, beyond the Company's control and which could, and likely will, materially affect actual results, levels of activity, performance or achievements. Any forward-looking statement reflects the Company's current views with respect to future events and is subject to these and other risks, including uncertainties and assumptions relating to the Company's operations, results of operations, growth strategy, and, among other things, liquidity. More detailed information about the Company and the risk factors that may affect the realization of forward-looking statements is set forth in the Company's most recent Annual Report on Form 10-K and other filings with the Securities and Exchange Commission. Investors and security holders are urged to read these documents free of charge on the SEC's website at http://www.sec.gov. Except as may be required by applicable law, the Company assumes no obligation to publicly update or revise these forward-looking statements for any reason, or to update the reasons actual results could differ materially from those anticipated in these forward-looking statements, whether as a result of new information, future events or otherwise. For further information: Matthew DuffyBrian KorbChief Business Officer, NRx PharmaceuticalsManaging Partner, astr Partnersmduffy@nrxpharma.com(917) 653-5122 brian.korb@astrpartners.com ____________________________ 1 https://www.ashp.org/drug-shortages/current-shortages/drug-shortage-detail.aspx?id=391 2 https://www.factmr.com/report/injectable-ketamine-market 3 https://www.radars.org/system/publications/NMURx%20Ketamine%20Use%20Poster_fin2.pdf
快速通道优先审批申请上市突破性疗法
2025-09-24
Suitability Petition is required for shift from multidose packaging of ketamine to single-patient dose preservative free ketamineGranting of Suitability Petition enables re-filing of Abbreviated New Drug Application (ANDA) for NRx’s patent-pending preservative-free ketamine product WILMINGTON, Del., Sept. 24, 2025 (GLOBE NEWSWIRE) -- NRx Pharmaceuticals, Inc. (Nasdaq:NRXP), a clinical-stage biopharmaceutical company, announced that it was notified yesterday by the United States Food and Drug Administration that a Suitability Petition has been granted for the strength proposed by the Company for its planned single-patient, preservative-free ketamine product (KETAFREE™). Currently, ketamine is sold in multi-dose vials that contain Benzethonium Chloride, a toxic preservative. The Suitability Petition that has been granted enables immediate re-filing of the Company’s Abbreviated New Drug Application for KETAFREE™. The Company believes that this proposed product addresses two critical policy objectives as articulated by the current administration: (1) the re-shoring of strategically important drugs, particularly sterile products from foreign manufacturing sources, and (2) the “Make America Healthy Again” (MAHA) objective of removing toxic preservatives and colorants from foods and drugs. These objectives have been articulated on numerous occasions by FDA and HHS leadership. The current market for ketamine is estimated at $750 million. The Company believes that its proposed KETAFREE™ product will be a successful offering in that market, wholly apart from the Company’s aim to supply a non-generic formulation of ketamine (NRX-100) as an innovative new drug to treat suicidal depression and PTSD under a New Drug Application. “Last week, NRx was honored to be selected to attend a ‘listening session’ hosted by the FDA Commissioner, for biotechnology CEOs. We appreciate FDA’s rapid response on the requested Suitability Petition and look forward to bringing our preservative-free presentation of ketamine to the US market at the earliest possible moment,” said Jonathan C. Javitt, MD, MPH, Chairman and CEO of NRx Pharmaceuticals. About NRx Pharmaceuticals, Inc.NRx Pharmaceuticals, Inc. (www.nrxpharma.com), is a clinical-stage biopharmaceutical company developing therapeutics based on its NMDA platform for the treatment of central nervous system disorders, specifically suicidal depression, chronic pain, and PTSD. The Company is developing NRX-100 (preservative-free intravenous ketamine) and NRX-101, (oral D-cycloserine/lurasidone). NRX-100 has been awarded Fast Track Designation for the treatment of Suicidal ideation in Depression, including Bipolar Depression. NRX-101 has been awarded Breakthrough Therapy Designation for the treatment of suicidal bipolar depression. NRx has recently had a Suitability Petition granted, allowing re-filing of an Abbreviated New Drug Application (ANDA), and initiated a New Drug Application filing for NRX-100 with an application for the Commissioner’s National Priority Voucher Program for the treatment of suicidal depression. Notice Regarding Forward-Looking StatementsThe information contained herein includes forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, and Section 27A of the Securities Act of 1933, as amended. Forward-looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, and include words such as "may," "will," "should," "would," "expect," "plan," "believe," "intend," "look forward," and other similar expressions among others. These statements relate to future events or to the Company's future financial performance, and involve known and unknown risks, uncertainties and other factors that may cause the Company's actual results to be materially different from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. The Company has reported regulatory milestones as they have been achieved but has not predicted the outcome of any future regulatory determination. You should not place undue reliance on forward-looking statements since they involve known and unknown risks, uncertainties and other factors which are, in some cases, beyond the Company's control and which could, and likely will, materially affect actual results, levels of activity, performance or achievements. Any forward-looking statement reflects the Company's current views with respect to future events and is subject to these and other risks, including uncertainties and assumptions relating to the Company's operations, results of operations, growth strategy, and, among other things, liquidity. More detailed information about the Company and the risk factors that may affect the realization of forward-looking statements is set forth in the Company's most recent Annual Report on Form 10-K and other filings with the Securities and Exchange Commission. Investors and security holders are urged to read these documents free of charge on the SEC's website at http://www.sec.gov. Except as may be required by applicable law, the Company assumes no obligation to publicly update or revise these forward-looking statements for any reason, or to update the reasons actual results could differ materially from those anticipated in these forward-looking statements, whether as a result of new information, future events or otherwise. For further information: Matthew DuffyChief Business Officer, NRx Pharmaceuticalsmduffy@nrxpharma.comBrian KorbManaging Partner(917) 653-5122brian.korb@astrpartners.co
快速通道突破性疗法
2025-09-22
·抗体圈
1
仁域
OX40与OX40L的分子特性与功能
1
OX40与OX40L的分子特性及表达特征
● OX40（CD134/TNFRSF4）
①分子结构：属于TNF受体超家族，是一种诱导性T细胞共刺激分子。 I型跨膜蛋白，含249个氨基酸，胞外区186个氨基酸，胞内区49个氨基酸，其编码基因定位于1p36染色体。
②表达调控：主要表达于活化的T细胞(CD8+效应T细胞、所有CD4+辅助T细胞亚型)、调节性T细胞(Tregs)、中性粒细胞及树突状细胞(DCs)，而在静息初始T细胞中不表达，在NK细胞、NKT细胞中低表达。其表达受TCR、CD28/CD80、CD40/CD40L等信号诱导，IL-2、IL-4、TNF等可增强或延长其表达，表达量在激活后的48-72小时达峰值。
● OX40L
①分子结构：属于TNF超家族，是OX40的特异性配体。 II型糖蛋白，含23个氨基酸胞内区、133个氨基酸胞外区，以三聚体的形式存在。
②表达调控：主要表达于抗原呈递细胞(APCs，如朗格汉斯细胞、树突状细胞、B细胞等)，同时也存在于血管内皮细胞及多种造血细胞(肥大细胞、固有淋巴细胞、NK细胞、活化T细胞)。其表达受TLR介导的炎症信号、CD40信号的调控，IL-18、IFN-γ、TSLP、前列腺素E2等可促进其表达。
2
OX40信号通路的激活机制及下游效应
● 信号激活机制
OX40L/OX40轴的激活依赖于抗原呈递细胞与T细胞的两步信号作用：
①初级信号：APCs通过表面的主要组织相容性复合体(MHC)将抗原呈递给T细胞表面的T细胞受体(TCR)，启动T细胞的初步活化。
②共刺激信号(次级信号)：激活后的APCs表达OX40L，与T细胞表面新表达的OX40特异性结合，形成OX40L-OX40复合物，为T细胞提供持续活化的关键信号。若缺乏该共刺激信号，T细胞将无法实现有效的增殖、存活及功能活化。
图1 APC激活T细胞启动OX40和OX40L表达
● 下游信号通路与效应
OX40L与OX40结合后，诱导OX40单体发生三聚化，招募TNF受体相关因子(TRAF)蛋白(如TRAF2、TRAF3、TRAF5等)，进而激活两条核心的下游信号通路，产生多重效应：
①核因子κB(NF-κB)通路：促进效应T细胞(Th1、Th2、Th17、Th22等)的增殖与分化，增强其向炎症部位的迁移和浸润。 刺激T细胞分泌多种促炎细胞因子，如Th2型的IL-4、IL-13，Th1型的IFN-γ，Th17型的IL-17，Th22型的IL-22等，加剧炎症。
②磷脂酰肌醇3-激酶(PI3K)/Akt通路：上调Bcl-xL、Bcl-2等抗凋亡分子的表达，延长效应T细胞的存活时间。 协同TCR促进Ca²⁺内流及NFATc1/NFATc2核转位，调控T细胞分化，诱导效应T细胞向长期存活的记忆T细胞转化。
3
OX40信号通路的核心功能
● 调控T细胞活性：作为共刺激分子，在免疫应答后期增强效应T细胞功能、维持其存活并抑制凋亡。 OX40信号对T细胞早期激活非必需，但可促进后期增殖与存活。
● 影响Th细胞分化：可诱导初始CD4⁺T细胞向Th2细胞分化，在抗原或IL-12存在时促进Th1分化； 通过激活TRAF6介导的非经典NF-κB通路参与Th9细胞分化； 同时可调控记忆T细胞，二次抗原刺激时快速上调表达，参与回忆应答。
● 调节免疫细胞成熟：反向信号(OX40L接收OX40信号)可促进DCs成熟，上调CD80、CD86等共刺激分子表达，增强IL-4、IL-6等细胞因子分泌； 还能促进B细胞增殖及免疫球蛋白分泌。
● 双向调控Treg细胞：一方面，OX40信号可抑制Treg细胞功能，下调Foxp3表达并减弱其对效应T细胞增殖的抑制； 另一方面，OX40激动剂可促进Treg细胞增殖，调控Treg细胞的发育。
● 参与免疫相关疾病：OX40/OX40L过表达与自身免疫病(如类风湿关节炎、格雷夫斯病)发病相关； 在移植物抗宿主病(GVHD)中，二者相互作用促进疾病发生发展； 同时参与抗病毒免疫应答，助力清除持续性病毒感染。
表1 OX40/OX40L在不同细胞类型中发挥作用
2
仁域
OX40信号通路在特应性皮炎(AD)中的作用
1
AD的免疫病理机制
AD的核心病理特征为T细胞介导的慢性炎症，涉及多条免疫通路：
● Th2：主导急性期炎症，与过敏反应相关。 分泌IL-4、IL-13(破坏皮肤屏障、促进IgE生成)、IL-31(直接激活感觉神经引发瘙痒)，且AD皮损中肥大细胞、2型固有淋巴细胞(ILC2)等Th2型细胞增多，进一步放大炎症。
● Th1：主要存在于慢性皮损，作用尚不完全明确。 分泌IFN-γ，但靶向其上游驱动因子IL-12的治疗对中重度AD无效，临床意义存疑。
● Th17：急慢性皮损中均有激活。 分泌IL-17A，导致皮肤屏障异常、上调S100A蛋白(具有抗菌和促炎作用)，但单独靶向IL-17A的治疗对AD效果不佳，甚至可能引发湿疹样不良反应。
● Th22：与AD严重程度相关。 分泌IL-22，介导表皮增生(皮肤屏障功能障碍的关键特征)，同时上调S100A蛋白，靶向IL-22的单抗在Ⅱ期试验中未达主要终点，仅在重症患者和早期时间点显效。
图2 OX40L/OX40在AD中的作用机制
2
OX40信号通路在AD发病各阶段的具体作用
● OX40/OX40L信号通路在AD中的表达规律
①AD中的表达异常：AD患者病变皮肤中，OX40L/OX40的表达水平及OX40L⁺细胞数量显著高于健康皮肤，其表达受AD皮损中高表达的警报素(如TSLP、IL-33)及皮肤金黄色葡萄球菌的病原体相关分子模式(PAMPs)调控。 且OX40L/OX40的表达量与AD疾病严重程度呈正相关，当AD治疗有效时，其表达水平及相关通路标志物会随之下降。
②细胞表达分布：在AD病变皮肤中，OX40L可表达于多种细胞，包括“专职”抗原提呈细胞(如朗格汉斯细胞、树突状细胞、B细胞)、“非专职”抗原提呈细胞(如角质形成细胞)，以及肥大细胞、2型固有淋巴细胞(ILC2)等。 OX40则主要表达于活化的效应T细胞(Th1、Th2、Th17、Th22亚型)和记忆T细胞表面。
● 急性期：驱动Th2主导的炎症启动与皮肤屏障破坏
AD急性期以Th2型炎症为主，OX40信号通路在此阶段的核心作用是放大Th2反应并破坏皮肤屏障：
①Th2细胞活化与扩增：皮肤屏障受损后，角质形成细胞释放TSLP、IL-25、IL-33等细胞因子，这些因子一方面直接激活APCs和ILC2，另一方面诱导APCs和ILC2表达OX40L。OX40L与初始T细胞表面的OX40结合，为T细胞活化提供共刺激信号，促进其向Th2细胞分化并大量扩增。
②皮肤屏障功能恶化：活化的Th2细胞分泌IL-4、IL-13，抑制角质形成细胞中丝聚蛋白等屏障相关基因的表达，同时促进表皮增生，进一步破坏皮肤屏障完整性。此外，Th2细胞分泌的IL-31可激活皮肤感觉神经元，引发瘙痒，而搔抓又会加剧屏障损伤，形成“炎症-屏障破坏-瘙痒”的恶性循环。
● 慢性期：促进炎症多极化与疾病慢性化、复发
AD进入慢性期后，炎症通路从单一Th2型向Th1、Th17、Th22多极化发展，OX40信号通路是这一转化的关键驱动力：
①炎症通路扩展：慢性期皮肤持续存在抗原刺激和促炎细胞因子(IL-1、IL-2、TNFα等)，这些信号维持OX40在活化T细胞上的高表达。 OX40信号不仅继续增强Th2反应，还通过激活NF-κB通路促进Th1、Th17、Th22细胞的存活和功能，导致IFN-γ(促进角质形成细胞凋亡)、IL-17(招募炎症细胞)、IL-22(诱导表皮增生)等细胞因子大量产生，加剧皮肤增厚、鳞屑、苔藓化等慢性病变。
②记忆T细胞介导的复发：OX40信号通路对记忆T细胞的形成和维持至关重要——效应T细胞在OX40信号作用下转化为皮肤驻留记忆T细胞(TRM)，这些细胞长期存在于皮肤中，一旦再次接触过敏原，可快速激活并分泌促炎细胞因子，引发AD复发。同时，循环中的记忆T细胞也可通过皮肤归巢特性迁移至病变部位，维持炎症慢性化。
图3 OX40信号在特应性皮炎发病机制中的作用
●全身炎症与共病关联
OX40信号通路的激活不仅局限于皮肤，还参与AD的全身炎症反应，与共病发生密切相关：
① 活化的T细胞在OX40信号驱动下分泌的促炎细胞因子(如IL-4、IL-13)进入血液循环，可作用于肺部、呼吸道等黏膜组织，促进过敏性鼻炎、哮喘等“特应性进行曲”相关共病的发生。
② 患者血液中OX40⁺T细胞比例与AD严重程度正相关，且其数量增加与全身炎症标志物(如C反应蛋白)升高同步，提示OX40信号通路是连接皮肤局部炎症与全身炎症的重要桥梁。
图4 OX40参与特应性皮炎的局部和全身炎症
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仁域
OX40信号通路的靶向治疗
1
靶向OX40信号通路的治疗意义
基于OX40信号通路在AD中的核心作用，阻断该通路可从多个维度改善疾病：
● 抑制多通路炎症：通过阻断OX40-OX40L相互作用，可同时减少Th1、Th2、Th17、Th22等多种致病性T细胞的数量和活性，降低其相关促炎细胞因子的分泌，实现“广谱”抗炎效果，避免单一靶向Th2通路(如度普利尤单抗)导致的炎症通路偏移(如Th1/Th17活化)。
●减少记忆T细胞形成：抑制OX40信号可削弱效应T细胞向记忆T细胞的转化，减少皮肤驻留记忆T细胞的数量，从而降低AD复发频率，延长缓解期。
● 修复皮肤屏障：通过减少IL-4、IL-13、IL-22等细胞因子的释放，可恢复角质形成细胞中屏障相关基因的表达，抑制表皮过度增生，促进皮肤屏障功能修复。
图5 OX40激动剂免疫疗法在TME中的影响
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靶向OX40信号通路的AD治疗药物
目前已有3种针对OX40或OX40L的单克隆抗体处于中重度AD临床研发阶段，早期临床研究显示出良好潜力。
● Rocatinlimab(AMG451/KHK4083)：非岩藻糖基化IgG1抗OX40单克隆抗体，可抑制并减少OX40+致病性T细胞数量。
● Telazorlimab(GBR830/ISB830)：人源化IgG1中和性抗OX40单克隆抗体，可阻断OX40与OX40L的相互作用。
● Amlitelimab(KY1005)：人IgG4抗体，可结合OX40L，阻断其通过OX40传递信号。
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OX40激动剂联合疗法的临床研究进展
图6 同步与序贯OX40激动剂免疫治疗方案的模型
● 与免疫检查点抑制剂(ICB)联合
ICB(如抗CTLA-4、抗PD-1/PD-L1)通过解除免疫抑制，与OX40激动剂的“免疫激活”作用形成互补，具体机制因ICB靶点不同而异：
①OX40激动剂+抗CTLA-4：抗CTLA-4在引流淋巴结增强肿瘤反应性T细胞初始活化，OX40激动剂则促进活化T细胞的增殖、存活及向肿瘤微环境(TME)浸润。 二者联合可特异性诱导Eomes⁺CD8⁺效应T细胞(表达转录因子Eomes，增强IFN-γ和颗粒酶B分泌)，此细胞群是该联合方案抗瘤活性的关键执行者。
②OX40激动剂+抗PD-1/PD-L1：OX40激动剂通过增强T细胞IFN-γ分泌，上调TME中PD-L1表达，为抗PD-1/PD-L1药物提供作用底物。
●与先天免疫激动剂联合
通过激活先天免疫细胞(如DCs、巨噬细胞)，为OX40激动剂激活的适应性免疫提供“启动信号”：
①OX40激动剂+IL-12：IL-12可促进DCs成熟、M1型巨噬细胞极化，同时增强OX40介导的T细胞存活。在肉瘤模型中，联合治疗使肿瘤特异性CD8⁺T细胞比例提升40%，但IL-12的严重毒性(如毛细血管渗漏综合征)限制其临床转化。
②OX40激动剂+TLR9激动剂(CpG)：CpG通过激活DCs分泌I型干扰素(IFN-α/β)，增强APCs的抗原提呈能力。在淋巴瘤、乳腺癌模型中，联合治疗可使TME中DCs的CD86表达量增加2倍，OX40⁺T细胞浸润密度提升3倍，且联合放疗可进一步放大“远隔效应”(非放疗部位肿瘤消退)。
●与放疗(RT)联合
放疗通过释放肿瘤抗原、激活cGAS/STING通路，为OX40激动剂创造“免疫原性TME”。 放疗诱导肿瘤细胞凋亡，释放肿瘤相关抗原(TAAs)，经APCs提呈后激活T细胞，OX40激动剂则促进这些活化T细胞的增殖与效应分化。 放疗后48小时内给予OX40激动剂效果最佳，此时TME中TAAs浓度最高，且DCs处于活化状态。
● 与其他T细胞激动剂联合
针对不同T细胞亚型的共刺激分子，实现“全方位”T细胞激活：
①OX40激动剂+4-1BB激动剂：OX40主要增强CD4⁺T细胞功能，4-1BB(CD137)优先激活CD8⁺T细胞和NK细胞。 联合治疗在黑色素瘤模型中可诱导“干细胞样”CD8⁺T细胞(高表达TCF1)，此类细胞兼具增殖能力和效应功能，使肿瘤无进展生存期延长2倍。
表2 已完成或终止OX40激动剂和联合治疗的临床试验
表3 OX40激动剂和联合治疗的积极临床试验
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新型联合治疗策略(临床前阶段)
针对现有方案缺陷，研究人员开发了多种创新联合策略，在动物模型中展现出显著潜力：
● OX40激动剂+IL-2激动剂：
①机制：IL-2激动剂(如IL-2/抗IL-2单抗复合物)优先结合CD122(IL-2Rβ链，高表达于CD8⁺T细胞/NK细胞)，增强OX40介导的T细胞存活与效应功能，同时减少传统高剂量IL-2的毒性。
②优势：下一代IL-2激动剂(如bempegaldesleukin)毒性显著低于传统IL-2，目前正探索其与OX40激动剂的联合，有望提升安全性与疗效。
● OX40激动剂+CTLA-4抑制剂+ITK抑制剂
①机制：OX40/CTLA-4联合可诱导Eomes⁺CD8⁺T细胞(关键效应细胞)，但Eomes表达受ITK(IL-2诱导T细胞激酶)-IRF4通路抑制； ITK抑制剂(如ibrutinib)可降低IRF4，解除Eomes转录抑制，进一步增强效应T细胞功能。
● OX40激动剂+精氨酸耗竭酶
①机制：精氨酸酶1(pegzilarginase)耗竭肿瘤微环境中的精氨酸(肿瘤细胞必需营养素)，直接诱导肿瘤细胞凋亡。 同时提升肿瘤细胞MHCI/II表达，增加TAAs提呈，为OX40激动剂激活T细胞提供“抗原基础”。
②突破点：激活T细胞可通过瓜氨酸-精氨酸挽救通路(LAT1转运瓜氨酸合成精氨酸)维持功能，避免精氨酸耗竭对T细胞的抑制。
● OX40激动剂+半乳糖凝集素-3(Gal-3)抑制剂
①机制：Gal-3是TME中的免疫抑制分子，通过抑制TCR信号、封存IFN-γ、促进M2型巨噬细胞极化，削弱免疫应答。 阻断Gal-3可逆转TME抑制，增强OX40激动剂介导的T细胞活化。
②临床转化基础：Gal-3抑制剂(belapectin)联合帕博利珠单抗已在黑色素瘤/头颈部鳞癌Ⅰ期试验中显示ORR提升至30%，为联合OX40激动剂提供依据。
● OX40激动剂+癌症疫苗
①机制：疫苗提供外源性TAAs，通过APCs提呈激活TCR信号，使T细胞表达OX40，进而响应OX40激动剂的共刺激信号，解决“抗原不足”问题。
②临床挑战：目前缺乏高效临床级癌症疫苗，个性化新抗原疫苗虽在临床试验中展现潜力(如NEO-PV-01)，但尚未与OX40激动剂联合验证。
4
仁域
OX40信号通路与自身免疫性疾病的关联
1
系统性红斑狼疮(SLE)
●表达异常：
①患者外周血CD4⁺T细胞OX40表达显著上调，且疾病活动指数(SLEDAI)与OX40⁺CD4⁺T细胞数量正相关。
②皮肤、肾脏等病变组织中，OX40L⁺髓系APCs(单核细胞、DCs)浸润增加，外周血OX40L⁺髓系细胞比例与循环Tfh细胞频率呈正相关。
● 病理机制：
①OX40信号激活SLE患者T细胞，上调Bcl-6、CXCR5、IL-21等Tfh相关分子，促进Tfh细胞分化及异位GC形成(如狼疮肾炎病灶中的Tfh样细胞聚集体)；
②OX40L⁺髓系细胞通过抑制Treg和滤泡调节性T细胞(Tfr)功能，解除对Tfh-B细胞轴的抑制，导致抗核抗体、抗dsDNA抗体等致病性自身抗体大量产生，引发肾脏、皮肤等多器官损伤。
● 治疗证据：动物实验中，抗OX40L单抗可降低狼疮模型小鼠(NZB/WF1)的自身抗体水平，减轻狼疮肾炎病理损伤。临床前研究显示，OX40L阻断可减少患者Tfh细胞活性及自身抗体分泌。
2
类风湿关节炎(RA)
● 表达异常：
①患者滑膜液、滑膜组织中的CD4⁺T细胞(尤其是CD4⁺CD28⁻记忆T细胞)OX40表达显著升高；
②滑膜组织衬里下细胞、外周血单核细胞及B细胞OX40L表达上调，且与滑膜炎症程度正相关。
●病理机制：
①OX40过表达的Tfh细胞(以Tfh17亚型为主)通过OX40信号增强IL-17分泌，促进滑膜炎症及关节损伤； 同时通过调控抗体唾液酸化，降低抗体抗炎活性，增强其致病性；
②OX40/OX40L信号激活滑膜组织中的APCs及效应T细胞，放大局部炎症，导致滑膜增生、软骨破坏及骨侵蚀。
● 治疗证据：胶原诱导关节炎(CIA)小鼠模型中，抗OX40L单抗可降低关节炎症评分，减少IFN-γ及抗Ⅱ型胶原抗体(IgG2a)产生； OX40Fab’-PEG阻断抗体可延迟关节炎发病，降低总体临床severity。
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1 型糖尿病 （T1D）
● 表达异常：
①新诊断T1D儿童外周血CD4⁺CD25highOX40⁺T细胞比例显著增加；
②非肥胖糖尿病(NOD)小鼠(T1D模型)发病前，胰腺淋巴结及脾脏中的CD4⁺/CD8⁺T细胞OX40表达已上调，发病后期胰腺淋巴结DCs的OX40L表达升高。
●病理机制：
①OX40/OX40L信号促进胰腺淋巴结中Tfh细胞分化，增强自身反应性B细胞活化，产生抗胰岛β细胞自身抗体(如抗谷氨酸脱羧酶抗体)；
②激活的OX40⁺效应T细胞向胰腺浸润，直接杀伤胰岛β细胞，导致胰岛素分泌不足，引发糖尿病。
● 治疗证据：12周龄NOD小鼠给予抗OX40L单抗可显著降低糖尿病发病率，减少胰腺组织中T细胞浸润及β细胞损伤。
4
格雷夫斯病(GD)
● 表达异常：
①患者循环CD4⁺T细胞OX40与OX40L共表达水平异常升高，且与促甲状腺素受体抗体(TRAb，致病性自身抗体)水平密切相关；
②甲状腺病变组织中存在OX40⁺Tfh细胞浸润。
● 病理机制：
①OX40/OX40L共表达增强CD4⁺T细胞的活化与存活，促进Tfh细胞辅助B细胞产生TRAb；
②TRAb结合甲状腺滤泡上皮细胞的促甲状腺素受体，持续激活甲状腺功能，导致甲状腺激素过度分泌，引发甲亢及甲状腺肿大。
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其他自身免疫病
● 多发性硬化(MS)：患者脑损伤组织中存在OX40⁺T细胞浸润，外周血IL-21分泌型Tfh样细胞增加； 实验性自身免疫性脑脊髓炎(EAE，MS模型)小鼠给予抗OX40L抗体后，临床评分降低，脊髓T细胞浸润减少。
● 干燥综合征(SS)：患者外周血CD4⁺T细胞OX40表达上调，B细胞及单核细胞OX40L表达升高； 唾液腺组织中Tfh细胞浸润增加，通过OX40信号促进B细胞活化，导致唾液腺炎症及分泌功能障碍。
● 重症肌无力(MG)：患者外周血CD4⁺T细胞及胸腺GC旁CD4⁺T细胞OX40表达升高，胸腺GC中存在OX40L⁺单核细胞； 循环Tfh细胞(尤其Tfh17亚型)增加，通过OX40信号增强抗乙酰胆碱受体抗体产生，导致神经肌肉接头功能异常。
表4 OX40、OX40L表达和Tfh细胞在自身免疫性疾病中的应用
表5 OX40/OX40L阻断剂在体内的治疗效果
5
仁域
OX40信号通路在恶性肿瘤中的作用
1
在肿瘤免疫中的作用机制
● 激活效应T细胞：OX40/OX40L结合增强TILs的增殖、存活及细胞因子(IFN-γ、IL-2)分泌，促进CD8⁺T细胞向肿瘤浸润，增强其细胞毒性； 在小鼠肉瘤、乳腺癌、结肠癌模型中，OX40激动剂可激活肿瘤特异性T细胞，诱导免疫记忆，抑制肿瘤生长。
● 重塑TME：OX40激动剂可减少TME中Treg细胞数量及功能，降低TGF-β等免疫抑制因子水平，减少髓系来源抑制细胞(MDSCs)和抑制性巨噬细胞浸润，营造促炎TME； 在小鼠肿瘤模型中，OX40激动剂可使瘤内CD8⁺T细胞增加、Treg细胞减少，逆转免疫沙漠型TME。
● 增强B细胞抗肿瘤作用：OX40L反向信号(B细胞OX40L接收T细胞OX40信号)促进B细胞增殖及抗体分泌，OX40L-Fc融合蛋白在小鼠肿瘤模型中可通过激活B细胞介导抗瘤效应。
2
OX40信号通路在不同肿瘤中的作用
图7 OX40和OX40配体在不同癌症类型的RNA表达模式
● 非小细胞肺癌(NSCLC)
①功能作用：OX40信号通过激活效应T细胞(CD4⁺/CD8⁺)增强抗肿瘤免疫，同时可能调控调节性T细胞(Treg)功能，若Treg高表达OX40则加剧免疫抑制； 可促进TILs增殖、存活及细胞因子分泌，增强局部免疫应答。 此外，与PD-1等免疫检查点分子存在负向关联，协同影响T细胞活性与TME免疫平衡。
②预后表达：CD8⁺效应T细胞高表达OX40提示良好预后(Ⅰ-Ⅲ期患者中，高OX40⁺TILs者OS更长)； Treg高表达OX40或OX40L高表达则预后不良； PD-1与OX40/OX40L共表达时，免疫抑制增强，预后恶化。
● 结直肠癌
①功能作用：CD8⁺T细胞上的OX40信号增强其细胞毒性，抑制肿瘤增殖； 可溶性OX40可能通过竞争性结合OX40L削弱膜结合OX40的共刺激作用，加剧免疫抑制； 此外，OX40/OX40L轴还参与调节TME中免疫细胞浸润与活化。
②预后表达：Ⅰ-Ⅲ期CD8⁺T细胞高表达OX40者OS、DFS显著延长，与肿瘤分化程度负相关； 晚期可溶性OX40升高者预后不良，与TME中OX40⁺Treg数量正相关。
● 卵巢癌
①功能作用：激活的OX40信号增强T细胞介导的抗肿瘤免疫，提升机体对肿瘤细胞的清除能力； 与化疗产生协同效应，通过增强免疫应答放大化疗对肿瘤细胞的杀伤作用。
②预后表达：复发患者OX40表达量高于初治患者，其高表达与更长无复发生存期及更高化疗应答率相关； 复发患者中，OX40高表达者化疗有效率显著提升，预后优于低表达者。
● 乳腺癌
①功能作用：肿瘤细胞上的OX40信号增强自身增殖、抗凋亡能力，促进疾病侵袭； OX40L⁺血小板通过增强Treg功能、加速血管生成，为肿瘤转移创造条件； 同时可激活效应T细胞，形成免疫应答与逃逸的平衡。
②预后表达：OX40表达与肿瘤分级正相关，其中肿瘤细胞高表达OX40或血小板高表达OX40L，均提示高肿瘤分级、转移倾向，预后不良； OX40⁺效应T细胞富集者预后相对较好。
●肝细胞癌(HCC)
①功能作用：OX40信号增强Treg细胞的免疫抑制功能，抑制效应T细胞活化与增殖，加剧TME免疫抑制； 与多种免疫检查点分子协同，削弱抗肿瘤免疫应答，促进肿瘤逃逸。
②预后表达：OX40主要高表达于Treg细胞，与血清甲胎蛋白(AFP)水平正相关，OX40L表达量低于其他肿瘤，与OX40⁺Treg数量无显著关联； 高OX40表达TME中，与LAG3、PD-1等多种免疫检查点分子共表达，形成多重免疫抑制。 Treg细胞高表达OX40者OS显著缩短； 叠加高AFP、多免疫检查点分子共表达时，预后进一步恶化，对治疗应答率低。
●急性髓系白血病(AML)
①表达与调控：OX40主要表达于白血病细胞(blast细胞)，通过激活NF-κB、PI3K-Akt通路，增强自身增殖、抗凋亡能力，加速疾病进展，且不依赖OX40L结合即可发挥作用。 OX40基因(TNFRSF4)与TP53、FLT3等不良突变共现，进一步强化促瘤效应。
②预后表达：OX40表达于白血病细胞，与细胞分化程度负相关； TME中OX40L表达与健康骨髓无差异，不参与OX40调控。 白血病细胞高表达OX40为独立不良预后标志物，OS、PFS显著缩短； 伴随不良突变时，化疗应答率低、复发风险高。
● 皮肤鳞状细胞癌
①功能作用：OX40信号增强Treg细胞对效应T细胞的抑制作用，削弱局部抗肿瘤免疫应答，为肿瘤侵袭和转移创造有利条件； 抑制TME中效应T细胞的浸润与活化，促进肿瘤逃逸。
②预后表达：OX40的表达量与肿瘤浸润深度、淋巴结转移状态正相关，转移灶中细胞密度高于原发灶。 OX40⁺Treg细胞富集者，肿瘤转移潜能增强，复发率高、OS短，预后不良。
3
OX40/OX40L单药治疗晚期恶性肿瘤的早期临床试验
表6 针对OX40/OX40L的已完成临床试验示例
表7 针对OX40/OX40L的活跃临床试验示例
6
仁域
OX40在常见皮肤病中的作用机制
1
特应性皮炎(AD)——Th2介导的炎症疾病
●病理关联：
①AD以皮肤2型炎症为核心，角质形成细胞分泌的胸腺基质淋巴细胞生成素(TSLP)激活DCs，诱导其表达OX40L并抑制IL-12，进而促进初始T细胞产生IL-3，通过嗜碱性粒细胞迁移和IL-4分泌加剧Th2炎症。
②AD患者皮肤CD4+T细胞OX40表达升高，真皮中OX40+细胞与OX40L+细胞共定位； 外周血中皮肤归巢CLA+CD4+T细胞OX40表达增加，提示OX40/OX40L信号维持慢性炎症。
●固有淋巴细胞(ILC2)的作用：AD皮肤中ILC2数量增多，受TSLP/IL-25/IL-33刺激分泌IL-5/IL-13； 虽皮肤中ILC2与OX40L的关联未明确，但肺部研究显示ILC2可通过IL-33依赖方式表达OX40L，平衡Th2细胞与Tregs增殖以调控炎症，推测皮肤中存在类似机制。
●临床研究进展：
①动物实验：OX40L阻断抗体可预防TSLP诱导的AD样炎症。
②KY1005(抗OX40L单抗)：完成Ⅱa期试验(NCT03754309)，结果未公布。
③KHK4083(抗OX40阻断单抗)：Ⅰ期试验显示安全性良好，可持续改善中重度AD病程。
④GBR830(抗OX40单抗)：Ⅱa期试验显示，可使湿疹面积和严重程度指数(EASI)降低50%，减少OX40+细胞和OX40L+DCs数量。
2
银屑病——Th17介导的炎症疾病
●病理关联：
①银屑病以3型炎症为核心，TNF-α激活的DCs分泌IL-23，稳定Th17细胞产生IL-17A/F，同时ILC3、中性粒细胞等也分泌IL-17A参与发病。
②银屑病皮损中OX40+细胞数量增加，但OX40对Th17的调控存在争议：OX40激动剂在实验性自身免疫性肠炎模型中抑制疾病活动，却在OVA诱导葡萄膜炎模型中通过促进Th17分泌IL-17A加剧中性粒细胞浸润。
③OX40调控皮肤Th17/Treg平衡：皮肤自然Tregs(nTregs)在IL-6/IL-23/IL-1β刺激下可向Th17分化，OX40信号通过抑制Th17相关基因表达维持Treg稳定性； OX40-/-CD27-/-双敲除Tregs在皮肤中数量减少，加剧白念珠菌诱导的3型炎症。
●临床研究进展：KHK4083(抗OX40单抗)在Ⅰ期试验中，可改善银屑病面积和严重程度指数(PASI)及静态医师整体评估(sPGA)评分。
3
斑秃(AA)——CD8+T细胞介导的自身免疫病
●病理关联：
①AA由细胞毒性CD8+T细胞攻击毛囊引起，毛囊通过免疫豁免(IP)逃避自身免疫，而IFN-γ等刺激激活的NKG2G+CD8+T细胞可突破IP。
②OX40L+肥大细胞在AA毛囊周围增多，与CD8+T细胞共定位； 肥大细胞高表达OX40L、4-1BB等共刺激分子，却低表达诱导Tregs的IL-10/TGF-β，通过OX40L激活CD8+T细胞分泌IFN-γ，同时削弱Tregs的免疫抑制功能。
●Tregs的作用：AA患者毛囊区域Foxp3+Tregs数量少于其他脱发疾病(如扁平苔藓性脱发)，外周血和毛囊周围CD39+Foxp3+Tregs减少； 低剂量IL-2治疗可促进Tregs增殖，部分患者实现毛发再生，但后续试验尚未验证。
●潜在标志物：重度AA患者血清OX40L水平降低，可作为局部免疫疗法(二苯环丙烯酮)疗效的预测指标。
4
天疱疮——Tfh细胞介导的自身免疫性大疱病
●病理关联：
①天疱疮由抗表皮细胞黏附蛋白(桥粒芯糖蛋白Dsg1/Dsg3)自身抗体引发，Tfh细胞分泌IL-21诱导记忆B细胞分化，其中分泌IL-17A的Tfh17细胞促进疾病活动和抗体产生。
②天疱疮患者皮肤驻留CD4+T细胞中，OX40与Tfh相关分子(ICOS、CD40L)、IL-17A、IL-21mRNA水平升高，这些细胞通过分泌IL-21诱导B细胞产生抗体； 外周血CD4+T细胞中OX40与Tfh标志物高表达，抗OX40阻断抗体可减少T细胞与B细胞共培养体系中的抗体产生。
●外周免疫耐受机制：动物模型中，Tregs通过自身OX40夺取迁移DCs表面的OX40L，导致Dsg3反应性T细胞因OX40信号不足而被清除，阻止其分化为Tfh等效应T细胞，提示OX40信号在autoreactiveT细胞活化中的关键作用。
图8 OX40/OX40L在皮肤病病理生理学中的可能作用
表8 OX40/OX40L轴在各种皮肤病中的功能
7
仁域
OX40靶向治疗的核心挑战与展望
1
关键挑战
●Tregs调控的复杂性：OX40在Tregs中的作用具有双向性，既可增强其免疫抑制功能(如抑制结肠炎)，也可削弱其抑制效应(如促进Th17分化)，具体效应依赖于细胞因子微环境，需进一步明确不同皮肤病中OX40对Tregs的调控机制。
●细胞类型的多样性：OX40L表达于DCs、肥大细胞、ILCs等多种细胞，不同细胞来源的OX40L对T细胞的调控可能存在差异(如ILC2来源OX40L平衡Th2与Tregs，肥大细胞来源OX40L抑制Tregs)，需针对性分析各疾病中核心效应细胞。
●疗效与安全性平衡：皮肤中OX40+Tregs数量丰富，OX40靶向治疗可能同时抑制效应T细胞与Tregs，需避免过度免疫抑制导致感染等风险，需通过精准剂量或联合治疗优化方案。
2
未来方向
●机制研究：深入解析不同皮肤病中OX40/OX40L轴涉及的细胞类型(如AD中的ILC2、银屑病中的ILC3)及信号通路，明确疾病特异性调控网络。
●临床转化：推进OX40靶向药物的Ⅲ期临床试验，探索单药或联合疗法(如与JAK抑制剂、PD-1抑制剂联用)在中重度皮肤病中的疗效； 开发伴随诊断标志物(如OX40L表达水平)，实现精准治疗。
●药物优化：设计具有细胞特异性的OX40激动剂/抑制剂(如仅靶向效应T细胞的OX40抗体)，减少对Tregs的影响，提升治疗安全性。
参考文献
Valenzuela F, Meza V. OX40/OX40L as a Therapeutic Target in Atopic Dermatitis: A Scoping Review. Biologics. 2025 May 2;19:281-288.
Guglielmo A, Borghi A, Zengarini C, Piraccini BM, Corazza M, Pileri A. OX40-OX40L Axis in Cutaneous T-Cell Lymphomas: Pathogenic, Prognostic, and Potential Therapeutic Perspectives. Biomolecules. 2025 May 13;15(5):715.
Schettini N, Pacetti L, Corazza M, Borghi A. The Role of OX40-OX40L Axis in the Pathogenesis of Atopic Dermatitis. Dermatitis. 2025 Jan-Feb;36(1):28-36.
Abdelhalim A, Yilmaz O, Elshaikh Berair M, Torres T. A Narrative Review of the OX40-OX40L Pathway as a Potential Therapeutic Target in Atopic Dermatitis: Focus on Rocatinlimab and Amlitelimab. Dermatol Ther (Heidelb). 2024 Dec;14(12):3197-3210.
Song R, Zhang H, Liang Z. Research progress in OX40/OX40L in allergic diseases. Int Forum Allergy Rhinol. 2024 Dec;14(12):1921-1928.
Marfil-Cantón M, Prados-Carmona A, Cebolla-Verdugo M, Husein-ElAhmed H, Campos F, Ruiz-Villaverde R. Anti-OX40 Biological Therapies in the Treatment of Atopic Dermatitis: A Comprehensive Review. J Clin Med. 2024 Nov 17;13(22):6925.
Thapa B, Kato S, Nishizaki D, Miyashita H, Lee S, Nesline MK, Previs RA, Conroy JM, DePietro P, Pabla S, Kurzrock R. OX40/OX40 ligand and its role in precision immune oncology. Cancer Metastasis Rev. 2024 Sep;43(3):1001-1013.
Guttman-Yassky E, Croft M, Geng B, Rynkiewicz N, Lucchesi D, Peakman M, van Krinks C, Valdecantos W, Xing H, Weidinger S. The role of OX40 ligand/OX40 axis signalling in atopic dermatitis. Br J Dermatol. 2024 Sep 18;191(4):488-496.
Croft M, Esfandiari E, Chong C, Hsu H, Kabashima K, Kricorian G, Warren RB, Wollenberg A, Guttman-Yassky E. OX40 in the Pathogenesis of Atopic Dermatitis-A New Therapeutic Target. Am J Clin Dermatol. 2024 May;25(3):447-461.
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| 适应症 | 国家/地区 | 公司 | 日期 |
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| 肺结核 | 美国 | 1964-06-29 |
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| 躁郁症 | 临床1期 | - | 2015-09-27 | |
| 精神分裂症 | 临床1期 | - | 2015-09-27 | |
| 肺外结核 | 临床1期 | 中国 | 2012-02-20 | |
| 泌尿道感染 | 临床1期 | 中国 | 2012-02-20 |
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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 |
|---|
临床4期 | 24 | (D-Cycloserine and Acetominophen) | 襯糧襯醖淵齋觸簾選鑰(夢廠蓋膚獵繭糧糧遞遞) = 糧鑰襯獵窪鹹窪夢壓憲 窪範膚簾壓鏇淵鬱製顧 (齋選製夢艱獵遞遞壓繭, 2.6) 更多 | - | 2023-05-17 | ||
Placebo (for D-cycloserine) (Placebo and Acetominophen) | 襯糧襯醖淵齋觸簾選鑰(夢廠蓋膚獵繭糧糧遞遞) = 築憲鹹鹹鹹餘糧糧鹽廠 窪範膚簾壓鏇淵鬱製顧 (齋選製夢艱獵遞遞壓繭, 1.5) 更多 | ||||||
临床2期 | 50 | iTBS plus placebo | 餘壓鏇淵鬱遞鏇鬱艱鑰(鏇艱鹽衊鏇鏇鹽鹹齋構) = 網獵網廠襯衊構鬱鑰積 鹹醖製鬱繭獵鹽廠齋簾 (選蓋範繭網繭廠鏇獵衊 ) 更多 | 积极 | 2022-10-12 | ||
iTBS plus D-cycloserine (100 mg) | 餘壓鏇淵鬱遞鏇鬱艱鑰(鏇艱鹽衊鏇鏇鹽鹹齋構) = 鬱鬱顧衊憲積鹽餘夢觸 鹹醖製鬱繭獵鹽廠齋簾 (選蓋範繭網繭廠鏇獵衊 ) 更多 | ||||||
N/A | 41 | (D-cycloserine) | 網觸醖製繭觸壓夢窪廠(構顧憲淵獵淵糧願顧壓) = 鏇積夢築襯繭觸膚壓醖 齋製壓憲觸簾鬱夢顧夢 (糧醖蓋繭鑰選艱齋壓窪, 32.31) 更多 | - | 2021-08-16 | ||
Placebo (Placebo) | 網觸醖製繭觸壓夢窪廠(構顧憲淵獵淵糧願顧壓) = 顧醖觸蓋壓鏇積壓繭憲 齋製壓憲觸簾鬱夢顧夢 (糧醖蓋繭鑰選艱齋壓窪, 25.06) 更多 | ||||||
早期临床1期 | 53 | (PSRT_DCS) | 齋窪簾獵願艱選構簾簾 = 繭蓋艱願簾簾簾淵製鏇 淵獵願蓋糧衊獵鬱遞積 (範廠壓齋夢糧淵鏇艱廠, 鹹衊窪鑰獵簾觸廠鬱蓋 ~ 襯簾衊齋淵膚憲觸顧夢) 更多 | - | 2021-05-19 | ||
Pill Placebo+Nicotine replacement therapy (PSRT_PBO) | 齋窪簾獵願艱選構簾簾 = 膚築獵築觸願窪製製蓋 淵獵願蓋糧衊獵鬱遞積 (範廠壓齋夢糧淵鏇艱廠, 範憲網夢膚衊鬱襯鹽網 ~ 憲遞淵鑰醖遞鑰簾蓋膚) 更多 | ||||||
早期临床1期 | 152 | Cognitive Behavioral Therapy+D-Cycloserine (Tailored Post-Session DCS) | 願膚觸蓋遞蓋觸繭糧網(壓構蓋齋淵襯廠襯鹽製) = 願鹹淵簾窪鹹範觸範獵 遞顧選糧遞製廠壓鏇遞 (鏇築積願鹹憲獵簾構簾, .13) 更多 | - | 2020-06-09 | ||
Cognitive Behavioral Therapy+D-Cycloserine (Pre-Session DCS) | 願膚觸蓋遞蓋觸繭糧網(壓構蓋齋淵襯廠襯鹽製) = 構遞鏇積鬱襯獵製鹹蓋 遞顧選糧遞製廠壓鏇遞 (鏇築積願鹹憲獵簾構簾, .13) 更多 | ||||||
临床3期 | 33 | 顧簾襯製鏇繭餘齋蓋鹹(願繭鑰簾簾窪壓鏇餘願) = 繭顧積鬱築網夢廠積艱 鹹築憲網廠構築願衊鏇 (糧糧憲憲襯獵齋製鹹醖 ) | - | 2020-06-01 | |||
Placebo | 顧簾襯製鏇繭餘齋蓋鹹(願繭鑰簾簾窪壓鏇餘願) = 醖夢壓積膚糧願餘願鏇 鹹築憲網廠構築願衊鏇 (糧糧憲憲襯獵齋製鹹醖 ) | ||||||
临床4期 | 111 | (Arm 1: Hydrocortisone) | 鑰艱廠觸餘製憲襯獵壓(糧獵衊網簾衊鑰醖鹹膚) = 淵夢齋夢鹹鑰廠齋衊製 網構顧簾鹽鹹壓簾夢鏇 (憲築繭製膚願衊餘鑰範, .0351212) 更多 | - | 2019-05-30 | ||
(Arm 2: D-Cycloserine) | 鑰艱廠觸餘製憲襯獵壓(糧獵衊網簾衊鑰醖鹹膚) = 構艱夢簾觸壓範襯製顧 網構顧簾鹽鹹壓簾夢鏇 (憲築繭製膚願衊餘鑰範, .0367306) 更多 | ||||||
N/A | 20 | (D-cycloserine + Habit Reversal Training) | 窪鑰鹹顧餘選憲醖醖鬱(餘觸鑰積獵鏇顧鏇齋觸) = 廠憲餘選簾夢願襯夢構 築糧壓鑰壓蓋憲廠製膚 (築蓋壓襯餘鑰構鏇範餘, 0.62) 更多 | - | 2019-04-25 | ||
Placebo (Placebo + Habit Reversal Training) | 窪鑰鹹顧餘選憲醖醖鬱(餘觸鑰積獵鏇顧鏇齋觸) = 繭淵廠遞觸觸襯鹹構鬱 築糧壓鑰壓蓋憲廠製膚 (築蓋壓襯餘鑰構鏇範餘, 0.54) 更多 | ||||||
临床3期 | 81 | Placebo (1 Placebo) | 壓糧餘繭鏇觸鬱鬱遞淵(顧齋餘選衊顧廠鹽壓簾) = 夢鑰觸窪網夢顧夢簾觸 鹽蓋積觸獵夢鏇築糧繭 (顧鹽鏇鏇觸齋簾艱積顧, 廠鬱顧夢製蓋膚遞選顧 ~ 鹹衊糧餘構製遞觸範鑰) 更多 | - | 2019-03-29 | ||
(2 Aripiprazole) | 壓糧餘繭鏇觸鬱鬱遞淵(顧齋餘選衊顧廠鹽壓簾) = 鑰餘衊築觸製蓋簾鑰願 鹽蓋積觸獵夢鏇築糧繭 (顧鹽鏇鏇觸齋簾艱積顧, 鏇糧夢糧選範廠繭鹹醖 ~ 獵壓淵繭簾選鑰糧糧齋) 更多 | ||||||
早期临床1期 | 68 | (D-cycloserine) | 糧淵選築網觸襯鏇製顧(觸醖觸顧憲廠夢鬱願鏇) = 壓願夢艱繭夢夢壓窪獵 膚築蓋齋齋鹹廠觸鏇築 (鹹襯鹽積襯齋製夢鏇觸, 6.8) 更多 | - | 2019-03-15 | ||
Placebo (Placebo) | 糧淵選築網觸襯鏇製顧(觸醖觸顧憲廠夢鬱願鏇) = 艱餘鏇蓋淵簾遞鏇構鏇 膚築蓋齋齋鹹廠觸鏇築 (鹹襯鹽積襯齋製夢鏇觸, 10.03) 更多 |
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