Tazarotene

导语 自身免疫性皮肤病（Autoimmune Skin Diseases, AISDs）属于慢性炎症性疾患，发病源于机体免疫系统发生识别紊乱，将皮肤自身组分判定为外源抗原，诱发自身抗体或效应免疫细胞应答，最终造成皮肤组织损伤。临床常见类型包含寻常型银屑病、特应性皮炎、白癜风以及大疱性类天疱疮等。 在该类疾病当中，银屑病患病群体规模大，全球约 2‑3% 人口受其困扰。该病病程迁延、无法彻底根治且复发率较高，会对患者躯体状态与心理层面造成双重压力。现阶段临床干预多以控制改善症状为核心，除外用制剂、物理及光疗等传统方案外，伴随生物技术发展，生物制剂、小分子药物等靶向系统治疗手段不断取得进展，持续推动银屑病治疗模式发生革新。 银屑病的发病机制 银屑病是一种由遗传易感性与环境触发因素（如感染、创伤或药物等）相互作用引发的慢性免疫介导性皮肤病，按临床表现和病程可分为寻常型银屑病，点滴状（散在型）银屑病，红皮病型银屑病，脓疱型银屑病和关节病型银屑病等多种类型。 银屑病主要是由于表皮角化细胞异常增生与分化失调，伴随皮肤屏障功能受损，促使先天免疫细胞如树突状细胞（Dendritic Cells, DCs）、皮肤巨噬细胞等激活并分泌白细胞介素23（Interleukin-23, IL‑23）、肿瘤坏死因子α（Tumor Necrosis Factor‑α, TNF-α）等促炎因子，诱导并维持辅助性T细胞17（T helper 17 cells, Th17）相关的免疫通路活化，进而刺激角化细胞产生更多促炎细胞因子和趋化因子，最终导致表皮厚化、鳞屑形成和血管扩张等典型病理与临床表现（图1）。 图1. 银屑病的发病机制 银屑病的临床现状 银屑病的临床治疗需结合疾病分型、皮损部位以及病情严重程度个体化给药。局限型斑块银屑病一般选用外用糖皮质激素、卡泊三醇等维生素 D 类似物或他扎罗汀；紫外线光疗适用于大面积皮损，但存在潜在致癌风险；重症患者或合并关节损害时，则需开展系统治疗，可选用甲氨蝶呤，羟基脲、6‑巯基嘌呤、硫唑嘌呤等免疫抑制剂，以及 PDE4 抑制剂阿普司特。 近二十年来，靶向促炎细胞因子的生物制剂，包括抗 TNF、抗 IL‑12/23、抗 IL‑17 与抗 IL‑23 单克隆抗体，凭借突出疗效与良好耐受性，已成为中重度银屑病的核心治疗手段。 与此同时，银屑病新药研发进程持续提速，多款新型口服小分子及新一代生物制剂陆续获批上市，大量口服候选药物也正处于临床开发阶段。 百时美施贵宝公司经FDA批准的选择性酪氨酸激酶2（Tyrosine kinase 2, TYK2）别构抑制剂Deucravacitinib展现出优于安慰剂与阿普司特的短期与长期疗效； 同时抑制IL‑17A，IL-17F的单抗Bimekizumab在多项Ⅲ期试验中取得极高的应答率； 口服IL‑17抑制剂（DC‑806及其衍生物DC‑853）、下一代高效PDE4抑制剂（Orismilast、ME3183）、口服肽类IL‑23受体抑制剂JNJ‑2113，及口服TYK2/JAK1抑制剂等在研管线均显示出潜在疗效与可接受的安全性（表1）。 总体趋势是更多靶向关键信号通路的口服与生物制剂并存，兼顾疗效、安全与给药便利性 。 表1. 部分已获批或在研的银屑病治疗药物 银屑病的新药研发策略 虽然银屑病治疗已有长足进步，但临床上仍存在诸多未被满足的需求。现有免疫抑制类药物存在感染、心血管异常乃至肿瘤发生风险，需要进一步降低用药不良反应；同时需提升长期疗效，减少停药后复发，简化维持治疗；还需要实现更高水平的皮损清除，开发针对难治及特殊部位皮损的精准治疗方案。 面对上述难题，药物研发走向多元，除迭代小分子与抗体药物外，多肽、细胞、微生物组等新型疗法也成为研究热点。 临床前体外实验与动物模型是银屑病新药开发的重要工具：体外细胞及共培养体系可解析药物作用机制，快速筛选候选化合物；动物模型能够模拟完整皮肤微环境，完成药效、给药方案及初步药代毒理评价；同时还可挖掘临床生物标志物，以此降低临床研发风险与成本。 案例分享1：Th17细胞体外功能模型 和咪喹莫特诱导的银屑病大鼠体内模型 在银屑病的发病机制中，CD4⁺ T 细胞亚群失衡是驱动慢性炎症的关键环节。药明康德生物学业务平台免疫中心团队建立了Th17细胞体外功能模型，用以评价候选药物对T细胞功能的调控作用。 首先，团队从外周血单个核细胞（Peripheral Blood Mononuclear Cell, PBMC）中分选CD4⁺ T 细胞，通过细胞因子混合物定向激活Th17细胞，同时加入一种泛JAK抑制剂 Tofacitinib，发现该抑制剂可显著抑制 T细胞增殖和IL-17A的释放，从而研究阻断JAK/STAT信号通路对T细胞功能的抑制效果，揭示其治疗机制并评估药效学和相关生物标志物（图3）。 图3. 体外Th17的激活和抑制 咪喹莫特为 TLR7 激动剂，可激活 TLR7 促使树突状细胞释放 IL‑23，进而启动 Th17 炎症通路。研究团队采用大鼠背部涂抹咪喹莫特乳膏的方式，构建与人银屑病表现相近的皮损模型，借助红斑、鳞屑、皮肤增厚等皮炎评分指标评价炎症严重程度。 实验结果显示，正常对照组大鼠皮肤无异常，模型组大鼠则出现红斑、鳞屑、表皮增厚等典型银屑病样表现；给予泛 JAK 抑制剂托法替布干预后，相关皮损症状得到明显改善（图 4A）。组织病理学检测也印证，模型组皮肤可见大量炎症细胞浸润、表皮增生增厚等银屑病特征性病理变化（图 4B）。 图4. 咪喹莫特诱导的银屑病大鼠皮肤病变 同时，观察到正常对照组大鼠皮肤正常，而模型组大鼠则临床PASI评分明显增加，经Tofacitinib干预后评分显著下降，三组间的临床评分表现出明显差异，提示本模型构建成功（图5）。而模型组与阳性给药组之间出现的治疗窗口，提示本模型可用于抗银屑病药物的药效验证。 图5. 咪喹莫特诱导的银屑病大鼠体重和临床评分 案例分享2：IL-23，IL-17体外 细胞激活模型和人源化小鼠体内模型 IL‑23/Th17/IL‑17 轴是银屑病发病的核心通路。IL‑23 推动 Th17 细胞分化增殖，该细胞分泌 IL‑17 等促炎因子；IL‑17 结合角质形成细胞表面 IL‑17R，诱导角质细胞异常增殖分化，并上调 CXCL1、CXCL2、CCL20 等趋化因子，放大皮肤局部炎症。 构建 IL‑23、IL‑17 体外细胞激活模型，评估候选药物对该通路的调控效果。检测 IL‑23 刺激下细胞 pSTAT3 水平，评价药物对 IL‑23 通路的抑制能力（图 6A）；借助报告基因细胞系快速筛选阻断 IL‑17‑IL‑17R 相互作用的抗体类分子（图 6B）；再开展角质细胞 IL‑17 激活试验，依据角质细胞释放的促炎因子水平，验证药物对 IL‑17 通路的实际功能抑制效果（图 6C）。 图6. IL-23, IL-17信号通路的体外功能检测 局部涂抹咪喹莫特的方式成功在B-hTL1A/hIL23A/hIL12B人源化小鼠模型上诱导出与人类银屑病相似的皮肤病变，建立银屑病小鼠体内模型。 实验结果显示正常对照组（Sham）小鼠皮肤完整、无红斑鳞屑；Vehicle 组小鼠第 3 天起出现明显红斑、厚鳞及皮肤增厚，第 7 天 PASI 总分显著增加，显著高于 Sham 组。 给予抗 IL-23 单抗 Guselkumab治疗的小鼠，皮损迅速缓解，PASI 分数显著低于 Vehicle 组（图7）。 图7. 咪喹莫特诱导的银屑病小鼠体临床评分和皮肤病变 同时，H&E 染色结果可见 Vehicle 组表皮显著棘层肥厚、角化不全及大量炎性细胞浸润；Guselkumab 治疗组则有显著改善，炎症浸润明显减少。 上述结果提示，利用咪喹莫特在 B-hTL1A/hIL-23A/hIL-12B 人源化小鼠建立银屑病模型；该模型对 IL-23 靶向治疗敏感，可适用于抗银屑病新药的临床前评价（图8）。 图8. 咪喹莫特诱导的银屑病小鼠的H&E染色 结语 综上，银屑病作为高发的慢性自身免疫性皮肤病，遗传与环境共同驱动 IL‑23/Th17/IL‑17 核心炎症通路异常激活，现有疗法虽已实现较大突破，但仍面临不良反应、停药易复发、特殊皮损难以清除等临床痛点，推动行业不断探索小分子、抗体、多肽等多元化研发方向。 临床前体内外模型是新药开发的关键支撑，Th17 细胞、IL‑23/IL‑17 体外评价体系，以及咪喹莫特诱导的大小鼠、人源化动物模型，能够高效完成靶点验证、药效评估与标志物挖掘。 完善的临床前研究平台可为银屑病创新药物的早期开发筑牢基础，助力更多安全有效的候选药物走向临床，满足患者尚未被满足的治疗需求。 长按识别左边二维码 关注我们了解更多 免责声明：本文部分图片及文字整理自网络，版权归原作者所有。如有侵权，联系删除，谢谢～

Video webcast now available here LA JOLLA, CA, Aug. 27, 2026 (GLOBE NEWSWIRE) -- GRI Bio, Inc. (NASDAQ: GRI) (“GRI Bio” or the “Company”), a biotechnology company developing innovative therapies for inflammatory, fibrotic and autoimmune diseases, today announced that it is featured in a "Why Now" video webcast. During the webcast, Marc Hertz, Ph.D., Chief Executive Officer of GRI Bio, discusses the Company's differentiated approach to treating idiopathic pulmonary fibrosis (IPF) through GRI-0621, a once-daily oral, RARβ/γ-selective agonist designed to modulate the biological pathways associated with inflammation, fibrosis and tissue repair. The discussion also highlights GRI-0621's differentiated mechanism of action and the significant unmet need that remains for patients living with IPF. As previously announced, GRI has been selected for presentation at the 2026 European Respiratory Society (ERS) Congress, being held September 5-9 in Barcelona, Spain, where it will present on data that it believes is supportive of GRI-0621’s differentiated mechanism and its potential to address the underlying biology of IPF. The video webcast is now accessible for on-demand viewing here. JTC Team and Virtual Investor Co. are paid consultants to GRI Bio, Inc. JTC Team and Virtual Investor Co. are investor relations and corporate communications firms. Any content included in this release shall not be construed as an offer to purchase securities of GRI Bio, Inc. Interested parties are responsible for conducting their own due diligence and are encouraged to review the Company's website and the SEC website for the latest information and filings on the Company. About GRI Bio, Inc. GRI Bio is a clinical-stage biopharmaceutical company focused on developing innovative therapies for inflammatory, fibrotic and autoimmune diseases. The Company’s lead program, GRI-0621, is an oral RARβ/γ-selective agonist being developed for the treatment of idiopathic pulmonary fibrosis (IPF), a progressive and life-threatening fibrotic lung disease with significant unmet need. GRI-0621 is designed to modulate pathways associated with inflammation, fibrosis and tissue repair and is being evaluated as a potential novel oral therapeutic for patients with IPF. In addition to GRI-0621, the Company is also developing a pipeline of novel type 2 diverse NKT (“dNKT”) agonists for the treatment of systemic lupus erythematosus. Additionally, with a library of over 500 proprietary compounds, GRI Bio has the ability to fuel a growing pipeline. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements may be identified by the use of words such as “anticipate,” “believe,” “contemplate,” “could,” “estimate,” “expect,” “intend,” “seek,” “may,” “might,” “plan,” “potential,” “predict,” “project,” “target,” “aim,” “should,” “will,” “would,” or the negative of these words or other similar expressions. These forward-looking statements are based on the Company’s current beliefs and expectations. Forward-looking statements include, but are not limited to, statements regarding: the Company’s expectations with respect to development and commercialization of the Company’s product candidates, the timing of initiation or completion of clinical trials and availability of resulting data, the potential benefits and impact of the Company’s clinical trials and product candidates and any implication that the data or results observed in preclinical trials or earlier studies, topline or interim data or trials will be indicative of results of later studies or clinical trials or final data, the Company’s beliefs and expectations regarding potential shareholder value and future financial performance, the Company’s beliefs about the timing and outcome of regulatory approvals and potential regulatory approval pathways, the Company’s expected future milestones, shareholder value and the length of time the Company’s current resources will fund its planned operations (which current estimate assumes only initial preparatory activities for GRI-0621 as substantial additional capital or resources will be required to fund future clinical trials of GRI-0621). Actual results may differ from the forward-looking statements expressed by the Company in this press release and consequently, you should not rely on these forward-looking statements as predictions of future events. These forward-looking statements are subject to inherent uncertainties, risks and assumptions that are difficult to predict, including, without limitation risks related to: (1) the Company’s inability to maintain the listing of the Company’s common stock on The Nasdaq Capital Market and to comply with applicable listing requirements; (2) changes in applicable laws or regulations; (3) the inability of the Company to raise financing in the future; (4) the success, cost and timing of the Company’s product development activities; (5) the inability of the Company to obtain and maintain regulatory clearance or approval for its respective products, and any related restrictions and limitations of any cleared or approved product; (6) the inability of the Company to identify, in-license or acquire additional technology; (7) the inability of the Company to compete with other companies currently marketing or engaged in the development of products and services that the Company is currently developing; (8) the accuracy of the estimated size and growth potential of the markets for the Company’s products and services, and its ability to serve those markets, either alone or in partnership with others; (9) that later data or clinical trials may be inconsistent with or contrary to data and observations to date, including that later data may not indicate a patient benefit, modulate toxicities or validate a mechanism of action; (10) inaccuracy in the Company’s estimates regarding expenses, future revenue, capital requirements and needs for and the ability to obtain additional financing; (11) the Company’s ability to protect and enforce its intellectual property portfolio, including any newly issued patents and its ability to obtain any expected patent term extensions, adjustments, exclusivities or disclaimers; and (12) other risks and uncertainties indicated from time to time in the Company’s filings with the U.S. Securities and Exchange Commission (the “SEC”), including the risks and uncertainties described in the “Risk Factors” section of the Company’s most recent Annual Report on Form 10-K filed with the SEC on January 30, 2026 and subsequently filed reports. Forward-looking statements contained in this announcement are made as of this date, and the Company undertakes no duty to update such information except as required under applicable law. Investor Contact:JTC Team, LLCJenene Thomas(908) 824-0775GRI@jtcir.com