Barzolvolimab

在抗体治疗方面，人们更多的是关注实体瘤相关的适应症，而自免疾病因其病程较长，且危重程度低而常常被忽视。随着医药科技的发展以及对自免领域的日益增多的关注，医药行业出现越来越多以自免为适应症的药物。近期，celldex公司发布了一篇名为“Dual Inhibition of Mast Cells and Thymic Stromal Lymphopoietin Using a Novel Bispecific Antibody, CDX-622”的研究性文章。该文章的核心内容是关于一种新型双特异性抗体（bsAb）CDX-622的研究，该抗体旨在同时抑制肥大细胞（Mast Cells,MCs）和胸腺基质淋巴细胞生成素（Thymic Stromal Lymphopoietin,TSLP）的活性，以治疗过敏性和炎症性疾病。文章详细描述了CDX-622的临床前研究。基础知识小栈肥大细胞（MCs）：位于皮肤、呼吸道、胃肠道和血管等组织中，能够快速响应外来刺激，释放多种介质（如组胺、蛋白酶等），会引发或加重过敏、炎症、自身免疫和纤维化疾病的病理生理过程，是组织驻留的先天免疫细胞。干细胞因子（SCF）：肥大细胞的存活需要其唯一配体干细胞因子（SCF）激活KIT受体，这在肥大细胞的激活、成熟和组织募集过程中发挥关键作用。胸腺基质淋巴细胞生成素（TSLP）：一种警报素，通过作用于树突状细胞、T淋巴细胞和2型天然淋巴细胞（ILC2），可引发强烈的2型炎症反应。TSLP还涉及其他疾病的发病机制，包括慢性阻塞性肺病（COPD）和纤维化。双特异性抗体（bsAb）：一种能够同时靶向两种不同抗原或配体的抗体，用于治疗多种疾病。临床前研究CDX-622：由针对SCF的单克隆抗体（SCF-12）和针对TSLP的单克隆抗体（1D10）组成。SCF-12通过阻断SCF与KIT的结合来抑制肥大细胞的激活，而1D10则通过阻断TSLP与其受体的结合来抑制TSLP介导的炎症反应。首先，研究人员分别测试了SCF-12和1D10的功能。SCF-12方面：中和干细胞因子（SCF）的单克隆抗体（mAb）SCF-12在体外抑制SCF/KIT活性的效力与barzolvolimab相当。(Barzolvolimab是一种人源化单克隆抗体，特异性结合并抑制KIT受体酪氨酸激酶的活性,通过高特异性结合KIT受体，抑制其配体干细胞因子（SCF）的结合，从而阻断KIT信号通路)SCF-12优先抑制可溶性SCF（sSCF)而非膜结合型SCF(mSCF)，并在体内降低了肥大细胞标志物。1D10方面：中和TSLP的单克隆抗体1D10的特性:1D10能够阻断TSLP与TSLPR的结合;抑制了TSLP依赖的CCL17从原代人树突状细胞（DCs）中的释放，并且抑制了表达TSLPR和IL17Rα的BaF3细胞的增殖，其效力与已获批的抗TSLP单克隆抗体tezepelumab相当。接下来，研究人员基于以上的结果构建了双抗CDX-622，并测试了其功能如下：双特异性抗体（bsAb）CDX-622对TSLP和SCF的抑制效力与其亲本单克隆抗体（mAbs）相当。1D10和CDX-622同样抑制了TSLP介导的人树突状细胞（DCs）中CD80表达的诱导、CCL17分泌的诱导，以及TSLP依赖的细胞增殖。SCF-12和CDX-622同样抑制了SCF依赖的KIT磷酸化，人肥大细胞脱颗粒，以及M-07e细胞增殖。CDX-622具有单克隆抗体（mAb）样的药代动力学特性，并在非人灵长类动物的皮肤中降低了肥大细胞（MC）标志物。在食蟹猴中，CDX-622在单次10 mg/kg静脉输注后表现出类似单克隆抗体（mAb）的药代动力学特性（n=3；显示为平均值±标准差）；CDX-622降低了耳部活检样本中的肥大细胞RNA标志物。CDX-622抑制了人皮肤中依赖于SCF和TSLP的炎症标志物。在活体人类皮肤样本中施用SCF+TSLP会导致与髓系细胞激活（CCL17/TARC、MRC1、CLEC4A）、上皮屏障功能（CAPN14、AREG）、瘙痒（IL31RA）和炎症细胞因子（IL19）相关的转录本上调。添加CDX-622会抑制这些标志物，其抑制程度与亲本单克隆抗体（mAbs）相似或更强。基因集富集分析（GSEA）证实，在给予SCF和TSLP后，许多通路被富集，包括肥大细胞（MC）激活、急性炎症反应和淋巴细胞信号传导。CDX-622广泛抑制了由SCF或TSLP诱导的通路。关键结论CDX-622这是一种新型双特异性抗体（bsAb），能够中和TSLP并通过抑制SCF来抑制肥大细胞。CDX-622具有以下特性：在体外实验中，CDX-622对TSLP和SCF依赖性活性的抑制效力与其亲本单克隆抗体（mAbs）以及tezepelumab或barzolvolimab相当。CDX-622优先抑制可溶性SCF而非膜结合型SCF，这可能对KIT依赖性过程产生不同的影响。在人体皮肤样本模型中，CDX-622能够抑制SCF和TSLP依赖性的炎症标志物。CDX-622具有单克隆抗体（mAb）样的药代动力学（PK）特性，并在非人灵长类动物的皮肤中显著降低了肥大细胞标志物。在一项良好实验室规范（GLP）毒理学研究中，CDX-622在所有剂量水平上均表现出良好的耐受性，其无明显毒性作用剂量（NOAEL）在高剂量水平75 mg/kg/剂量下得以确定，并在多种组织中显著减少了肥大细胞。CDX-622有望改善TSLP和SCF起协同作用的疾病的治疗效果。目前正在进行一项在健康受试者中进行的单剂量和多剂量递增的两项研究（NCT06650761）。Cell dex认为，使用针对KIT的抑制性抗体（barzolvolimab）减少组织中肥大细胞数量，在慢性荨麻疹治疗中已显示出早期的临床潜力；中和TSLP已在嗜酸性粒细增多性和非嗜酸性粒细增多性哮喘中显示出临床活性，因此，同时中和驱动慢性炎症的互补通路，可能比单一靶点抑制获得更好的临床效果。关于BarzolvolimabBarzolvolimab是Cell dex目前管线中另一款临床研究药物，目前最快正处于临床3期研究中，涵盖多种适应症，是一种特异性结合KIT受体的人源化单克隆抗体。研究意义这项研究提供了一种新的治疗策略，通过同时靶向肥大细胞和TSLP，可能改善现有单靶点疗法的局限性，为治疗复杂的过敏性和炎症性疾病提供了新的希望。参考资料来源于企业官网。欢迎感兴趣的朋友进群讨论，群二维码如下：推文用于传递知识，如因版权等有疑问，请于本文刊发30日内联系医药速览。原创内容未经授权，禁止转载至其他平台。有问题可发邮件至yong_wang@pku.edu.cn获取更多信息。©2021 医药速览 保留所有权利往期链接“小小疫苗”养成记 | 医药公司管线盘点 人人学懂免疫学| 人人学懂免疫学（语音版）综述文章解读 | 文献略读 | 医学科普|医药前沿笔记PROTAC技术| 抗体药物| 抗体药物偶联-ADC核酸疫苗 | CAR技术| 化学生物学温馨提示医药速览公众号目前已经有近12个交流群（好学，有趣且奔波于医药圈人才聚集于此）。进群请扫描上方二维码，备注“姓名/昵称-企业/高校-具体研究领域/专业”，此群仅为科研交流群，非诚勿扰。简单操作即可星标⭐️医药速览，第一时间收到我们的推送①点击标题下方“医药速览”  ②至右上角“...”  ③点击“设为星标

77% of patients (150 mg Q4W) treated with barzolvolimab who had angioedema at baseline were angioedema free at Week 52 Data further support barzolvolimab clinical benefit to patients with CSU June 14, 2025 -- Celldex Therapeutics, Inc. (NASDAQ:CLDX) today announced data demonstrating that barzolvolimab profoundly improves angioedema at 52 weeks in the Company’s Phase 2 clinical trial in chronic spontaneous urticaria (CSU). Angioedema, characterized by swelling of the deeper dermal layers of the skin and mucous membranes, is a painful, debilitating symptom of CSU that has significant impact on quality of life. It commonly affects the face (lips and eyelids), hands, feet, and genitalia but can also involve the tongue, uvula, soft palate, and pharynx1. The data were presented today by Dr. Martin Metz, Professor, Department of Dermatology and Allergy, Head of Translational Research and Deputy Head of Clinical Trials at Charité – Universitätsmedizin in Berlin, in an oral presentation at the European Academy of Allergy and Clinical Immunology (EAACI) Congress 2025. Celldex previously announced that the Phase 2 study in CSU met its primary and secondary endpoints at 12 weeks with clinically meaningful and statistically significant decreases in UAS7 (weekly urticaria activity score) compared to placebo across multiple dose groups, including improvements in quality of life and angioedema measurements, and demonstrated a favorable safety profile. The data presented today further support these results by demonstrating improvements in AAS7 (weekly angioedema activity score) and additional measures of angioedema control over the 52 week treatment period. AAS7 measures the frequency and intensity of angioedema episodes, where higher scores indicate increased angioedema activity. “The majority of patients with severe CSU suffer with angioedema, which is often extremely painful and causes disfigurement, dramatically impacting quality of life,” said Diane C. Young, MD, Senior Vice President and Chief Medical Officer of Celldex Therapeutics. “Consistent with previously reported clinical outcomes, we observed rapid, profound angioedema relief with barzolvolimab treatment and this benefit continued to improve over 52 weeks of therapy for patients. These data add to the unprecedented 76 week efficacy and safety data we presented yesterday at EAACI and continue to support barzolvolimab’s potential to redefine the treatment landscape and meet the goals of CSU therapy—rapid, profound, durable complete response and improved quality of life across a broad patient population.” Patients on study had severe CSU. Over 70% of patients had a weekly urticaria activity score (UAS7) greater than 28 at baseline and reported very high rates of angioedema at baseline. Barzolvolimab demonstrated rapid, robust and durable improvements in angioedema symptoms over the treatment period. At Week 52, an 86% mean reduction from baseline was reported for 150 mg Q4W arm and an 82% reduction was reported for the 300 mg Q8W. Up to 77% of patients treated with barzolvolimab who had angioedema at baseline were angioedema free (AAS7=0) at Week 52. Patients treated with barzolvolimab were angioedema free up to 72% of the time over the 52 week treatment period. Up to 87% of patients reported clinically meaningful improvement (>8 point) in AAS7 at Week 52. Barzolvolimab is a humanized monoclonal antibody that binds the receptor tyrosine kinase KIT with high specificity and potently inhibits its activity. KIT is expressed in a variety of cells, including mast cells, which mediate inflammatory responses such as hypersensitivity and allergic reactions. KIT signaling controls the differentiation, tissue recruitment, survival and activity of mast cells. In certain inflammatory diseases, such as chronic urticaria, mast cell activation plays a central role in the onset and progression of the disease. Barzolvolimab is currently being studied in chronic spontaneous urticaria (CSU), chronic inducible urticaria (CIndU), prurigo nodularis (PN), eosinophilic esophagitis (EOE) and atopic dermatitis (AD), with additional indications planned for the future. The randomized, double-blind, placebo-controlled, parallel group Phase 2 study evaluated the efficacy and safety profile of multiple dose regimens of barzolvolimab in patients with CSU who remain symptomatic despite antihistamine therapy, to determine the optimal dosing strategy. 208 patients were randomly assigned on a 1:1:1:1 ratio to receive subcutaneous injections of barzolvolimab at 75 mg every 4 weeks, 150 mg every 4 weeks, 300 mg every 8 weeks or placebo during a 16-week placebo-controlled treatment period. After 16 weeks, patients then entered a 36-week active treatment period, in which patients receiving placebo or the 75 mg dose were randomized to receive barzolvolimab 150 mg every 4 weeks or 300 mg every 8 weeks; patients already randomized to the 150 mg and 300 mg treatment arms remained on the same regimen as during the placebo-controlled treatment period. After 52 weeks, patients entered a follow-up period for an additional 24 weeks. Barzolvolimab achieved the primary efficacy endpoint of the study—a statistically significant mean change from baseline to Week 12 in UAS7 (weekly urticaria activity score) compared to placebo at all dose levels. Celldex is currently conducting a global Phase 3 Program for barzolvolimab in CSU, consisting of two Phase 3 trials (EMBARQ-CSU1; NCT06445023 and EMBARQ-CSU2; NCT06455202) designed to establish the efficacy and safety of barzolvolimab in adult patients with CSU who remain symptomatic despite H1 antihistamine treatment. The studies also include patients who remain symptomatic after treatment with biologics. Enrollment is underway. CSU is characterized by the occurrence of hives or wheals for 6 weeks or longer without identifiable specific triggers or causes. The activation of the mast cells in the skin (release of histamines, leukotrienes, chemokines) results in episodes of itchy hives, swelling and inflammation of the skin that can go on for years or even decades. Current therapies provide symptomatic relief only in some patients. Celldex is pioneering new horizons in immunology to deliver life-changing therapies. We are relentless in our pursuit of novel antibody-based treatments that engage the human immune system and directly affect critical pathways to improve the lives of patients with allergic, inflammatory and autoimmune disorders. The content above comes from the network. if any infringement, please contact us to modify.