更新于：2024-11-01

IL-21

更新于：2024-11-01

基本信息

别名

IL-21、IL21、interleukin 21

+ [2]

简介

Cytokine with immunoregulatory activity. May promote the transition between innate and adaptive immunity. Induces the production of IgG(1) and IgG(3) in B-cells (By similarity). Implicated in the generation and maintenance of T follicular helper (Tfh) cells and the formation of germinal-centers. Together with IL6, control the early generation of Tfh cells and are critical for an effective antibody response to acute viral infection (By similarity). May play a role in proliferation and maturation of natural killer (NK) cells in synergy with IL15. May regulate proliferation of mature B- and T-cells in response to activating stimuli. In synergy with IL15 and IL18 stimulates interferon gamma production in T-cells and NK cells (PubMed:11081504, PubMed:15178704). During T-cell mediated immune response may inhibit dendritic cells (DC) activation and maturation (By similarity).

关联

项与 IL-21 相关的药物

Avizakimab

靶点

IL-21

作用机制

IL-21抑制剂

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

IL-21 mab(Eli Lilly & Co.)

靶点

IL-21

作用机制

IL-21抑制剂

在研机构

Eli Lilly & Co.

原研机构

Eli Lilly & Co.

在研适应症

免疫系统疾病

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

Latikafusp

靶点

IL-21 x PD-1

作用机制

IL-21抑制剂 [+1]

在研机构

Amgen, Inc. [+1]

原研机构

Amgen, Inc.

在研适应症

实体瘤 [+1]

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

项与 IL-21 相关的临床试验

NCT06198296 / Not yet recruiting临床1期IIT

Immunotherapy For Adults With GPC3-Positive Solid Tumors Using Interleukin-15 And -21 Armored Glypican-3-Specific Chimeric Antigen Receptor Expressing Autologous T Cells

The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells.
Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise but have not been strong enough to cure most patients.
In order to get them to kill cancers more effectively, in the laboratory, the study team inserted a new gene called a chimeric antigen receptor (CAR) into T cells that makes them recognize cancer cells and kill them. When inserted, this new CAR T cell can specifically recognize a protein found on solid tumors, called glypican-3 (GPC3). To make this GPC3-CAR more effective, the study team also added two genes called IL15 and IL21 that help CAR T cells grow better and stay in the blood longer so that they may kill tumors better. When the study team did this in the laboratory, they found that this mixture of GPC3-CAR,IL15 and IL21 killed tumor cells better when compared with CAR T cells that did not have IL15 plus IL21 in the laboratory. This study will use those cells, which are called 21.15.GPC3-CAR T cells, to treat patients with solid tumors that have GPC3 on their surface.
The study team also wanted to make sure that they could stop the 21.15.GPC3-CAR T cells from growing in the blood should there be any bad side effects. In order to do so, they inserted a gene called iCasp9 into the FAST-CAR T cells. This allows us the elimination of 21.15.GPC3-CAR T cells in the blood when the gene comes into contact with a medication called AP1903. The drug (AP1903) is an experimental drug that has been tested in humans with no bad side-effects. This drug will only be used to kill the T cells if necessary due to side effects .
The study team has treated patients with T cells that include GPC3. Patients have also been treated with IL-21 and with IL-15. Patients have not been treated with a combination of T cells that contain GPC3, IL-21 and IL-15. To summarize, this study will test the effect of 21.15.GPC3-CAR T cells in patients with solid tumors that express GPC3 on their surface.
The 21.15.GPC3-CAR T cells are an investigational product not yet approved by the Food and Drug Administration.

开始日期2026-01-01

申办/合作机构

Baylor College of Medicine

[+1]

ACTRN12622001449729 / Recruiting临床1期

A Randomized, Double-blind, Placebo-controlled Phase I Study to assess the safety and tolerability of Subcutaneous EQ102 Administered in a Single and Multiple Ascending Dose Schedule.

开始日期2022-09-30

申办/合作机构

Equillium AUS Pty Ltd.

NCT05156034 / Terminated临床1期

A Randomized, Placebo-Controlled, Double-blind, Multiple Dose, Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics Following Intravenous Administration of SRK-001 in Healthy Participants

The purpose of the study is to evaluate safety, tolerability, and pharmacokinetics (PK) of SRK-001 in Healthy Participants.

开始日期2021-12-21

申办/合作机构

Sarkana Pharma, Inc.

100 项与 IL-21 相关的临床结果

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100 项与 IL-21 相关的转化医学

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0 项与 IL-21 相关的专利（医药）

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3,998

项与 IL-21 相关的文献（医药）

2024-12-01·International Immunopharmacology

VSIG4 induces the immunosuppressive microenvironment by promoting the infiltration of M2 macrophage and Tregs in clear cell renal cell carcinoma

Article

作者: Yang, Lijun ; Zheng, Xiwang ; Shao, Ying ; Lan, Yan ; Ma, Yanjie ; Yang, Tao ; Duan, Lianrui ; Tong, Tong ; Chen, Wenjing ; Liu, Hangfeng

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma and has a poor prognosis. Despite the impressive advancements in treating ccRCC using immune checkpoint (IC) blockade, such as PD-1/PD-L1 inhibitors, a considerable number of ccRCC patients experience adaptive resistance. Therefore, exploring new targetable ICs will provide additional treatment options for ccRCC patients. We comprehensively analyzed multi-omics data and performed functional experiments, such as pathologic review, bulk transcriptome data, single-cell sequencing data, Western blotting, immunohistochemistry and in vitro/in vivo experiments, to explore novel immunotherapeutic targets in ccRCC. It was found that immune-related genes VSIG4, SAA1, CD7, FOXP3, IL21, TNFSF13B, BATF, CD72, MZB1, LTB, CCL25 and KLRK1 were significantly upregulated in ccRCC (Student's t test and p-value < 0.05; 36 normal and 267 ccRCC tissues in raining cohort; 36 normal and 266 ccRCC tissues in validation cohort) and correlated with the poor prognosis of ccRCC patients (Wald test and p-value < 0.05 in univariate cox analysis; log-rank test and p-value < 0.05 in Kaplan-Meier method; 267 patients in training cohort and 266 in validation cohort). In particular, we found the novel IC target VSIG4 was specifically expressed in inhibitory immune cells M2-biased tumor-associated macrophages (TAMs), conventional dendritic cell 2 (cDC2) cells, and cycling myeloid cells in ccRCC microenvironment. Moreover, VSIG4 showed a closely relation with resistance of Ipilimumab/Nivolumab immunotherapy in ccRCC. Furthermore, VSIG4 promoted the infiltration of M2 macrophages, Tregs, and cDC2 in ccRCC tissues. VSIG4⁺ TAMs and VSIG4⁺ cDC2s may be a kind of immune cell subtypes related to immunosuppression. VSIG4 may play similar roles with other IC ligands, as it is highly expressed on the surface of antigen-presenting cells and ccRCC cells to inhibit T cells activity and facilitate immune escape. Targeting IC gene VSIG4 may provide a novel immunotherapeutic strategy to ccRCC patients with resistance to existing targeted therapy options.

2024-12-01·Immunology Letters

IL-21 drives skin and lung inflammation and fibrosis in a model for systemic sclerosis

Article

作者: Cho, Mi-La ; Lee, Seon-Yeong ; Um, In Gyu ; Park, Sung-Hwan ; Na, Hun Sik ; Jeong, Ha Yeon ; Lee, Jeong Su ; Woo, Jin Seok ; Lee, A Ram ; Lee, Young Joon

BACKGROUNDSystemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, abnormal inflammation, and fibrosis of the skin and internal organs, notably the skin and lungs, significantly impairing quality of life. There is currently no cure for SSc, and its etiology remains largely unknown, presenting a primary barrier to effective treatment. We investigated the role of interleukin-21 (IL-21) in the pathogenesis of SSc.METHODSWe assessed the expression levels of fibrosis-related genes in human dermal fibroblasts exposed to IL-21 and TGF beta. We also induced SSc in wild-type C57BL/6 mice and IL-21 knockout (KO) mice with a C57BL/6 background using bleomycin (Bleomycin). Histological analyses were conducted on skin and lung tissues from these mice. The distribution and expression levels of fibrosis-related proteins in the tissues were examined via immunohistochemistry and quantitative real-time PCR. Furthermore, we measured the frequency of Th1, Th2, and Th17 cells among splenocytes through flow cytometry.RESULTSIL-21 activation led to STAT3 phosphorylation more than TGF beta in dermal fibroblasts. In IL-21 KO mice with BLM-induced SSc, skin thickness and lung fibrosis were reduced. The absence of IL-21 in these mice resulted in suppressed expression of fibrosis-related genes, including Col1a1, Col1a2, Col3a1, CTGF, α-SMA, STAT3, and TGFβ, in the skin and lungs. It also led to a decreased frequency of Th1, Th2, and Th17 cells, as well as a lower Th17/Treg ratio among splenocytes, factors known to contribute to the development of SSc.CONCLUSIONSIL-21 contributes to the development of SSc by promoting the expression of fibrosis-related genes and modulating the levels of CD4+ T cells.

2024-12-01·Molecular Therapy - Nucleic Acids

Cell-targeted gene modification by delivery of CRISPR-Cas9 ribonucleoprotein complexes in pseudotyped lentivirus-derived nanoparticles

Article

作者: Shah, Jagesh V ; Thomsen, Emil Aagaard ; Rovsing, Anne Bruun ; Degn, Søren Egedal ; Nielsen, Ian Helstrup ; Mikkelsen, Jacob Giehm ; Nedergaard, Frederikke ; Boesen, Thomas ; Shah, Jagesh V. ; Bøggild, Andreas ; Møller, Charlotte Thornild ; Ruzo, Albert ; Janns, Jacob Hørlück

To fully utilize the potential of CRISPR-Cas9-mediated genome editing, time-restricted and targeted delivery is crucial. By modulating the pseudotype of engineered lentivirus-derived nanoparticles (LVNPs), we demonstrate efficient cell-targeted delivery of Cas9/single guide RNA (sgRNA) ribonucleoprotein (RNP) complexes, supporting gene modification in a defined subset of cells in mixed cell populations. LVNPs pseudotyped with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein resulted in angiotensin-converting enzyme 2 (ACE2)-dependent insertion or deletion (indel) formation in an ACE2⁺/ACE2^- population of cells, whereas Nipah virus glycoprotein pseudotyping resulted in Ephrin-B2/B3-specific gene knockout. Additionally, LVNPs pseudotyped with Edmonston strain measles virus glycoproteins (MV-H/F) delivered Cas9/sgRNA RNPs to CD46⁺ cells with and without additional expression of SLAM (signaling lymphocytic activation molecule; CD150). However, an engineered SLAM-specific measles virus pseudotype (measles virus-hemagglutinin/fusion [MV-H/F]-SLAM) efficiently targeted LVNPs to SLAM⁺ cells. Lentiviral vectors (LVs) pseudotyped with MV-H/F-SLAM efficiently transduced >80% of interleukin (IL)-4/IL-21-stimulated primary B cells cultured on CD40 ligand (CD40L)-expressing feeder cells. Notably, LVNPs pseudotyped with MV-H/F and MV-H/F-SLAM reached indel rates of >80% and >60% in stimulated primary B cells, respectively. Collectively, our findings demonstrate the modularity of LVNP-directed delivery of ready-to-function Cas9/sgRNA complexes. Using a panel of different pseudotypes, we provide evidence that LVNPs can be engineered to induce effective indel formation in a subpopulation of cells defined by the expression of surface receptors.

219

项与 IL-21 相关的新闻（医药）

2024-10-30

·PipelineReview

Anaveon announces presentation of new data on development compounds ANV700 and ANV600 at the Society for Immunotherapy of Cancer 2024 Annual Meeting

– First presentation of ANV700, a targeted IL-21 employing proximity activated potentiation of cytokine signaling – – New mechanistic data provide insights into the mode of action of ANV600, currently in clinical development – BASEL, Switzerland I October 30, 2024 I Anaveon, a clinical stage, immuno-oncology company, today announced that it will present posters on ANV700 and ANV600 at the Society for Immunotherapy of Cancer (SITC) 39th Annual Meeting being held from Friday, November 8, 2024, to Sunday, November 10, 2024, in Houston, Texas. “ANV700 is a novel powerful PD-1 targeted therapeutic which focuses IL-21 signaling on T cells in the tumor microenvironment with the potential to reverse exhaustion,” said Christoph Huber, Chief Scientific Officer of Anaveon . “We will further develop this molecule towards clinical studies to determine the therapeutic benefit in patients.” Posters will be available on the virtual meeting platform and at anaveon.com beginning Nov. 7 at 9 a.m. CST. Details of the poster presentations: Saturday, Nov. 9, 12:15 – 1:45 pm CST Poster #960 Title: ANV700 is a novel proximity-activated IL-21 receptor agonist designed to selectively reinvigorate tumor-reactive PD-1 expressing T cells Authors: A. Rau, N. Egli, P. Murer, L. Petersen, C. Stocker, K. Richter, C. Huber Poster #954 Title: ANV600, a cis-signaling αPD-1/IL-2Rβ/γ agonist, expands both CD4+ and CD8+ tumor-specific T cells by acting in the tumor microenvironment and draining lymph nodes Authors: P. Murer, A. Zurbach, L. Petersen, N. Egli, A. Katopodis, C. Huber Anaveon is developing selective cytokine receptor agonists with the potential to therapeutically enhance a patient’s immune system to respond to tumors. ANV419, currently in Ph II studies in multiple cancer indications, is designed to preferentially signal through the IL-2 beta/gamma receptor resulting in strong proliferation of effector cells in patients. The follow-on compound, ANV600, targets the selective IL-2 receptor moiety to intratumoral effector cells and may have therapeutic benefit in less immunogenic tumors. These novel types of therapeutics, if approved, could potentially have a wide utility in oncology, including in combination with checkpoint inhibitors, cell therapies, vaccines, and radiotherapy. About Anaveon: Anaveon is a biotechnology company located in Basel, Switzerland. Using our immunological knowledge and expertise in protein engineering, we develop medicines to deliver meaningful benefits to cancer patients. Our lead compounds, ANV419 and ANV600, are currently in clinical trials in solid tumors. Find out more at > anaveon.com SOURCE: Anaveon

免疫疗法AACR会议临床2期临床1期

2024-10-29

·凯莱英Asymchem

【关注】CAR-E，走上历史舞台

来源：同写意在全球首款CAR-T细胞产品Kymriah上市刚好七年的今天，CAR系列疗法依然一刻不停地频繁变革。光CAR-T就已更迭到第五代——通用型CAR-T，试图突破个体限制，实现规模化生产和治疗，使用BBIR CAR或SUPRA CAR等方式降低成本；CAR-NK，还在验证阶段，但已有创新者率先探索CAR-NKT的可行性；CAR-M，巨噬细胞也在近两年正式加入CAR疗法行列，有效性和安全性仍有待在临床治疗中验证。在每个月好几场的行业大会中，上述疗法或多或少均有探讨，不算太新鲜。但实验室里悄悄发生的变化，正以更惊人的速度改变人类战胜癌症的征途。 7月30日，Nature Biotechnology的一篇论文描述，Dana-Farber癌症研究所的科学家们创造了一种CAR-Enhancer（简称CAR-E）疗法，可以根除肿瘤细胞并增强CAR-T细胞的记忆。该研究成果或将解决CAR-T疗法使用后癌症复发的问题。具体作用机制是，通过增强CAR-T细胞的活跃度，延长在体内的持续时间，使它们能够保持战斗模式，直到所有肿瘤细胞都被消除（如果癌症复发，它们就重新发挥作用）。这种技术被命名为CAR-E，在一些患者来源的癌细胞系实验和其他研究中，CAR-E确实联合CAR-T成功根除了所有肿瘤细胞。那么，这种CAR-E如何设计与开发？对CAR-T有怎样的作用？是否还有其他增强方案？下文将详细探讨。 1 CAR-E对CAR-T的作用研究人员构建了一种融合蛋白，该融合蛋白由人BCMA蛋白胞外结构域与低亲和力突变人IL-2二聚体（称为“mutIL-2”）融合而成。 mutIL-2分子包含两个取代（H16A和F42A），可降低其对人IL-2Rβ的亲和力（3倍；K型D~610 nM）和IL-2Rα（CD25）（110倍；K型D~1200 nM）（见下图）。因此，BCMA-mutIL-2融合蛋白通过抗原与CAR特异性结合，优先将低亲和力的IL-2分子递送至CAR-T细胞表面，从而最大限度地减少对正常T细胞、调节性T细胞或全身毒性的影响。图a CAR-E治疗平台示意图。左图：CAR-E的总体设计。右图：开发的BCMA-mutIL-2 CAR-E的结构。图b BCMA-mutIL-2 CAR-E与BCMA CAR-T细胞结合，具有高特异性和亲和力。为改善药代动力学和增强稳定性，研究者在抗原和mutIL-2分子之间整合了人免疫球蛋白G1（IgG1）的CH3结构域（大小约为14kDa）。该研究中，研究者评估了BCMA CAR-E对BCMA CAR-T细胞的功能影响。结果表明，CAR-T细胞上CD69的表达呈剂量依赖性和选择性增加，而对非转导的T细胞没有观察到影响。此外，与VHH-mutIL-2、BCMA-CH3或其组合相比，BCMA CAR-E处理导致CD69表达显著增加，这表明观察到的效果仅在低亲和力IL-2分子与抗原融合时才明显。同时，BCMA CAR-E不抑制CAR-T细胞的杀伤效果。研究者在不同浓度的BCMA CAR-E存在下，使用CAR-T细胞和患者来源的BCMA OPM2癌细胞进行了杀伤试验。结果表明，即使在CAR-E的最高测试浓度（100 nM）下，也不会抑制杀伤效果。综上，BCMA CAR-E通过顺式递送低亲和力IL-2对靶向CAR-T细胞产生影响，其作用由抗原与CAR结合介导。紧接着，该研究通过MM异种移植小鼠模型，探究CAR-E治疗对CAR-T细胞体内持久性的影响。CAR-E治疗不仅增强了CAR-T细胞的持久性，而且还改善了肿瘤细胞的消除。在接受BCMA CAR-T细胞治疗的患者中，复发仍然是一个主要问题。可以看到，这一研究将增强分子递送给CAR-T细胞，由BCMA胞外域与低亲和力IL-2融合的BCMA CAR-E增强了BCMA CAR-T细胞的活性和持久性。 CAR-E可以指导CAR-T细胞发育具有不同表型的记忆细胞，并不依靠肿瘤细胞的存在实现这一作用。CAR-E导致产生一系列不同的记忆亚型，包括干细胞记忆群体。这种多样性可能是观察到的CAR-T细胞长期持续存在的原因，这些CAR-T细胞在再刺激时保留了重新扩增的能力。CAR-E的这种能力可能归因于其作用机制，同时参与IL-2R和CAR（4-1BB–CD3ζ）内域。该研究通过多种方式证明CAR-E选择性地增强了CAR-T细胞的功能和持久性。这种方法提供了一种现成的治疗选择，使得产业应用层面可以优化剂量和治疗计划。 2 引导变革的增强子在该研究之前，解决复发问题的研究许多都集中在重新设计CAR-T细胞本身，例如引入或消除基因使细胞保持更长时间的活性，但仍未出现有效的临床证明。 Dana-Farber的研究员们没有试图改变CAR-T细胞的内部运作，而是开发了一种从外部起作用的方法——将一种分子输送到细胞面前，延长细胞的寿命并促使它们形成记忆。实验发现，CAR-E疗法不仅能够促使CAR-T细胞增殖，而且能够产生具有不同特性的不同类型的CAR-T细胞。 “它不仅产生了大多数患者已经拥有的效应T细胞，而且还产生了干细胞样记忆T细胞，中央记忆T细胞，效应记忆T细胞——对癌症产生有效免疫反应所需的T细胞种类的完整库，”Dana-Farber的Mohammad Rashidian解释道，在骨髓瘤细胞的实验室培养和该疾病的动物模型中，CAR-E疗法实现了肿瘤细胞的完全清除。研究者还发现，该疗法产生的长效CAR-T细胞可以通过重新给予CAR-E来重新刺激。这表明，CAR-T细胞治疗后复发的患者可以通过额外剂量的CAR-E治疗得到有效治疗。此外，CAR-E还提出了一种可能性，即患者可以用比目前更少的CAR-T细胞数量进行治疗。目前，使CAR-T细胞繁殖成数亿个的做法，往往耗时、昂贵，需要大量资源，且患者需要等待数周才能接受细胞注射。大剂量往往容易造成CAR-T细胞疗法最常见的副作用之一——细胞因子释放综合征，过度激进的免疫反应会导致发烧、恶心、心跳加快、神经系统问题或其他问题。 Rashidian博士认为，使用CAR-E，可以完全跳过CAR-T细胞扩增过程，简单地制造CAR-T细胞并将其注入患者体内，然后用CAR-E治疗。目前，CAR-E疗法临床试验的首要目标，是确保安全性并确定最佳剂量和给药时间周期。最初，他们预计CAR-E治疗将在患者输注CAR-T细胞后大约一个月开始，每周一次，持续三到四周。可以看出，这种疗法的一个好处是，可以轻松地整合到目前已接受CAR-T细胞疗法的患者的护理中，对于解决CAR-T细胞耗竭问题也是一种解决方案。或许我们能尽快在临床试验中看见CAR-E的身影。 3 增强CAR-T的6种策略在CAR-E出现之前，增强CAR-T效果一直是科研界的热门话题。公认的策略是将CAR-T细胞与其他现有疗法相结合，开发能增强CAR-T疗效、减轻毒性、扩大治疗范围的联合疗法。被誉为“CAR-T之父”的Carl June，今年7月25日在Cancer Cell发布了一篇综述，详细介绍了在临床试验阶段的CAR-T联合治疗策略。其中增强CAR-T疗效的联用方案如下： 01 靶向免疫检查点的抗体将免疫检查点抑制剂（ICI）与CAR-T疗法结合，提高TME内CAR-T细胞的寿命和功效。目前，在B细胞淋巴瘤等血液癌中，CAR-T细胞与ICI联合的临床试验展现了高反应率和可控的毒性水平。但应用时机对于治疗效果来说至关重要，有试验表明，在CAR-T细胞输注前启动抗PD-L1抗体疗法，整体的治疗效果不佳。 02 肿瘤靶向抗体及BiTE 这一策略的核心思路在于双靶向或多靶向，意图将靶向CD20（或CD3/CD20）的抗体与靶向CD19/BCMA的获批CAR-T产品相结合，有效地根除肿瘤细胞并降低抗原逃逸风险。目前，利妥昔单抗与CAR-T联合使用的多项临床实验正在开展，展现出初步的良好结果。 03 小分子药物已有小分子药物获批用于治疗血液癌症和实体瘤，其中一些与CAR-T联合使用的临床试验正在进行中。比如，伊布替尼与CAR-T联合使用的临床试验初步结果表明，这种联合方法对TP53突变的慢性淋巴细胞白血病（CLL）患者收益明显。靶向蛋白质降解剂来那度胺（lenalidomide）和CAR-T的联合疗法在最近的临床试验中显示，治疗多发性骨髓瘤的耐受性良好，总体反应率达到100%。 04 癌症疫苗癌症疫苗可以激活免疫系统以对抗癌细胞，在与CAR-T联用时，有可能增强CAR-T细胞的活化、增殖和持久性。在最近的一项I/II期临床试验中，利用RNA疫苗增强CAR-T细胞的策略展现出良好的初步结果——21名实体瘤患者的疾病控制率为67%，表现出使用癌症疫苗增强CAR-T细胞持久性的潜力。 05 溶瘤病毒溶瘤病毒能够在肿瘤细胞中选择性复制，同时保留健康细胞。将溶瘤病毒与CAR-T联合使用时，临床前研究已经显示出克服肿瘤免疫抑制的潜力。目前，临床试验正在评估这种组合方法在实体瘤中的疗效。 06 放射性疗法放射性治疗广泛适用于不同类型的肿瘤、非侵入性以及消除肿瘤细胞。在一项针对复发性或难治性弥漫大B细胞淋巴瘤（DLBCL）的CAR-T疗法II期临床试验中，在CAR-T细胞治疗之前接受放疗的患者实现了100%的反应率。这一结果表明，放射性治疗可以作为CAR-T治疗前的减瘤和桥接方案，以及复发后治疗的选择。此外，该论文还介绍了细胞因子在增强CAR-T疗效中的潜力。CAR-T细胞经过改造可以表达细胞因子，提高疗效和持久性。分泌IL-12、IL-15、IL-18、IL-21等细胞因子的CAR-T细胞临床试验目前已在进行中。然而，上述这些联用方案和本文开头介绍的CAR-E增强子方案，都还需要进一步探索如何降低毒性，并找到最佳的给药方案。参考资料： 1.A Novel Way to Prevent Relapse After CAR-T Therapy to Treat Cancer；Cancer Health 2.Rakhshandehroo, T., Mantri, S.R., Moravej, H. et al. A CAR enhancer increases the activity and persistence of CAR T cells. Nat Biotechnol (2024). 3.Ugur Uslu et al., CAR T cell combination therapies to treat cancer. Cancer Cell (2024).

细胞疗法免疫疗法临床结果临床研究

2024-10-29

·CPHI制药在线

中医药调控 JAK/STAT 信号通路治疗银屑病的研究进展

关注并星标CPHI制药在线 JAK-STAT通路与银屑病的发生、发展密切相关，作为银屑病治疗的补充疗法和替代药物，当代中医药的应用研究证明了其治疗银屑病的有效性。研究发现，中药单体、中药有效成分、中药复方和针灸对银屑病治疗中 JAK-STAT 通路均有明显调节作用。 1、中药单体、有效成分通过 JAK-STAT 通路调控治疗银屑病多种中药单体或有效成分可通过调节JAK-STAT通路参与银屑病的发生发展，主要为苷类、生物碱类，它们通过调节JAK-STAT 通路而纠正银屑病免疫失调，减轻炎症反应，进而控制病情。厚朴酚为木脂素类化合物，提取自厚朴，具有抗炎、抗菌、抗过敏等作用。研究发现，厚朴酚能抑制咪喹莫特诱导银屑病小鼠血清IL-17、IL-23水平，从而降低TNF-α、JAK/STAT ( JAK2/STAT3) 、NF-κB 等蛋白表达，进而对小鼠银屑病皮损具有良好的改善作用。麻黄具有抗炎、抗菌、抗过敏等作用，可应用于多种临床疾病的治疗。麻黄的主要成分为盐酸麻黄碱、盐酸伪麻黄碱、盐酸甲基麻黄碱等生物碱。应用麻黄单味药物的水煎剂灌胃咪喹莫特诱导的银屑病小鼠模型，发现麻黄可以改善银屑病皮损组织病理下的角化过度和炎性浸润，降低银屑病病理评分系统（Baker）和银屑病皮损面积及严重程度指数（PASI）的分值，其机制与降低血清中 IL-6 的含量，抑制皮损中 IL-6、IL-17A、IL-17C mRNA 的表达，降低皮损中 STAT3、p-STAT3蛋白含量相关。雷公藤多苷提取自雷公藤，具有抗炎、免疫抑制、调节免疫等作用。研究报道，雷公藤多苷可降低银屑病小鼠血清 TNF-α、IL-17、IL-23 水平及银屑病皮损组织 JAK1、STAT3 蛋白表达，抑制 JAKs-STAT 信号通路的活化，进而改善皮损炎症。人参皂苷是人参中提取的天然化合物，具有抗炎、调节免疫作用。研究发现，人参皂苷可降低咪喹莫特诱导银屑病小鼠血清 p-JAK1、p-JAK2、p-STAT3 表达，降低炎症因子IL-23、IL-17水平，抑制JAK1/2STAT3活化。氧化苦参碱是提取自苦参、山豆根等的活性生物碱，具有抗病毒、抗炎、免疫调节等作用。研究表明，氧化苦参碱可通过降低炎症因子TNF-α、IFN-γ、IL-6、IL-8 水平，升高SOCS1 表达来抑制JAK1、STAT3 表达，阻碍JAK/STAT 信号通路激活，进而抑制KC 增殖，调节T淋巴细胞活化、平衡，从而达到治疗银屑病的目的。丹皮酚是牡丹皮、徐长卿的主要有效成分，具有抗炎、抗肿瘤、代谢调节、镇痛等作用。丹皮酚可降低咪喹莫特诱导的银屑病小鼠皮损 microRNA-155、STAT3、IL-17、IL-23、IFN-γ 水平，升高SOCS1 表达，从而干预 JAK/STAT 及其下游 IL-2、IL-4、IL-6、IFN-γ 等细胞因子来发挥免疫效应。紫草素为萘醌类化合物，提取自紫草，具有抗菌、抗炎等作用。紫草素能够通过STAT3 信号通路抑制IFN-γ 诱导的IL-17过度分泌，并阻断 JAK2/STAT3信号通路，抑制银屑病小鼠模型皮损部位VEGF 表达，也可抑制树突状细胞分泌细胞因子 IL-23，抑制Th17特异性免疫应答，从而发挥治疗银屑病的作用。此外，研究发现商陆皂苷甲能有效降低银屑病模型小鼠外周血 IL-17、IL-22、IL-6、TNF-α 水平。白芍总苷可降低银屑病患者外周血IL-17、IL-22、IL-23 水平。土大黄提取物能调节咪喹莫特诱导银屑病小鼠模型IL-23/IL-17轴。洋金花提取物可抑制银屑病小鼠 IL-17、TNF-α、NF-κB 等细胞因子水平，从而降低 IL-23、IL-8、IL-6 水平，还可升高 IL-10 水平。落新妇苷能抑制咪喹莫特诱导的银屑病小鼠的Th17细胞分化，减少IL-17 释放，削弱Th17 细胞的JAK/STAT3 信号转导。 2、中药复方通过JAK-STAT 通路调控治疗银屑病清热利湿饮、加味凉血消风散、蜈蚣败毒饮等可通过 JAK-STAT 通路参与银屑病的发生、发展，其功效主要包括清热、利湿、凉血、解毒、祛风、止痒等。清热利湿饮为中医经方龙胆泻肝汤的变方，由龙胆草、黄芩、柴胡、牡丹皮、当归、金银花、土茯苓、泽泻、栀子、生地黄、车前子、甘草等组成，研究表明，该中药方剂可以从动物学和细胞学2个角度抑制IL-6的表达及其介导的JAK1/STAT3信号通路的激活，并可以影响下游IL-17A 的分泌水平，改善动物模型中银屑病样的炎症反应。此外，研究发现该方剂对于IL-22、JAK1、TYK2、p-STAT3、STAT3等参与该通路中诱导、调控、磷酸化、信号终端的多个因子均具有干预作用。消银解毒颗粒由水牛角、生地黄、牡丹皮、赤芍、忍冬藤、大青叶、紫草、甘草等组成，作用于体外经植物血凝素（PHA）和 IL-6 共同诱导的人T淋巴细胞瘤细胞（Jurkat），结果发现，经IL-6刺激后Jurkat细胞的增殖能力显著提升，以10 μg·L-1质量浓度时的增殖作用最为明显，中药方剂及其拆方均能够显著影响 JAK1、STAT3、gp130共3个指标的基因及蛋白表达量，该实验较为精确的描绘出 IL-6/JAK1/STAT3 信号通路从诱导刺激、到受体结合、再到信号激活的整体过程，也体现出中医药凉血解毒法作用的核心机制。凉血消银颗粒剂由紫草、赤芍、白花蛇舌草、丹参、槐花、生地、白茅根、水牛角、鸡血藤、丹皮、熟地黄组成，具有清热凉血、活血化瘀的功效。研究表明，凉血消银颗粒剂可以降低银屑病模型小鼠血清TNF-α、IL-1、IL-6、IL-23水平，升高SOCS1表达，从而缓解银屑病症状。加味凉血消风散由水牛角、生地黄、牡丹皮、连翘、僵蚕、地骨皮、紫荆皮、冬桑叶、白花蛇舌草、玄参、女贞子、旱莲草、炙甘草等组成，研究证实，该方剂可以通过下调 JAK3/STAT3信号通路，下调抑凋亡基因，上调促凋亡基因，从而诱导细胞凋亡来达到缓解银屑病的目的。中药复方制剂加味凉血消风散在 JAK/STAT 信号通路的 3 个家族亚型中均发挥调节作用，包括IL-21介导的 JAK3/STAT3 环节、IL-22及IFN-γ 分别介导的 JAK/STAT 环节，该方剂的配伍体现中医学在血分症疾治疗中的“入血就恐耗血动血，直须凉血散血”的辨证理念和“治风先治血，血行风自灭”的治疗先机，以凉血为核心，用养阴之妙法，散血热，祛风盛，以其治疗急性进展期银屑病，将中医理论围绕 JAK/STAT 信号通路家族进行了系统融合，也为同类方剂的微观机制系列研究提供了较好的借鉴和思路。楮芍凉血汤由楮桃叶、白芍、连翘、黄连、金银花、黄芩、生地黄、威灵仙、白花蛇舌草、细辛等组成，对血热证银屑病患者进行了机制研究，结果显示其可以通过调控 JAK3/STAT3 信号通路，改善银屑病的 PASI 分值及灼热、瘙痒、心烦等一系列血热症状。养血解毒汤由土茯苓、生地黄、板蓝根、丹参、当归、麦冬、玄参、鸡血藤、草河车、车前子组成，对银屑病模型鼠皮损组织中 JAK3、p-JAK3、STAT3、p-STAT3的表达及 Th17 相关因子 IL-17A、IL-17C、IL-22、维甲酸受体相关孤儿受体 γ（t RORγt）进行对照研究，发现以凉血养血活血、祛湿解毒的名家验方可以抑制 STAT3 的磷酸化，减少Th17 细胞相关因子的分泌，由此改善模型的银屑病样皮损。丹参白疕消丸由丹参、乌梢蛇、全蝎、土鳖虫、大黄、蝉蜕、徐长卿、山楂、板蓝根、红花、防风、苦参、黄柏、蜈蚣、甘草等组成，其主要功效为养血活血。在干预银屑病鼠模型中发现其药物提取液能够分别降低外周血中IL-23、IL-17、IL-22、IL-6的浓度及皮损中上述因子的mRNA 表达水平，并下调皮损中STAT3的蛋白表达量，进一步提取鉴定发现，该方剂的有效成分为丹酚酸B、丹参酮Ⅱ A、盐酸小檗碱、升麻素苷、苦参碱、甘草酸铵等。蜈蚣败毒饮由蜈蚣、紫草、土茯苓、鬼箭羽、乌梢蛇、甘草等组成，对银屑病小鼠模型血清、皮损组织中SOCS1、JAK2、STAT3，及其上游微小核糖核酸-155（microRNA-155）和下游Treg 细胞主导通路 IL-2-叉头框蛋白 P3（FoxP3）-IL-10/转化生长因子-β（TGF-β）进行研究，发现该方剂可以调控以 microRNA-155 介导的 SOCS1-JAK2/STAT3 信号通路从而影响 Treg 细胞功能，改善银屑病模型的皮损指数评分。 3、中医外治法通过JAK-STAT 通路调控治疗银屑病体内外实验结果表明，针灸、艾灸、火针、热敏灸可通过JAK-STAT 通路参与银屑病的发生、发展，其主要具有抗炎、调节免疫的作用。艾灸能够刺激人体的免疫系统，其温热功效能影响免疫细胞、免疫因子，改善免疫功能。研究发现，艾灸可以降低咪喹莫特诱导的银屑病模型小鼠血清 IL-17A水平，抑制皮损组织 TNF-α、IL-1β、IL-6 mＲNA 表达，提示艾灸可降低炎性因子水平，抑制炎性反应，调节免疫功能，进而促进银屑病皮损的改善。火针具有激发经气、扶正祛瘀、通经活络的作用。研究发现，火针可降低咪喹莫特诱导的银屑病模型小鼠皮损组织 IL-17、IL-22、TNF-α mRNA 表达，抑制 pSTAT3 表达，进而抑制 STAT3通路活化，减轻炎性细胞浸润，改善银屑病皮损。此外，研究发现，热敏灸可降低咪喹莫特诱导的银屑病模型大鼠外关穴筋膜 JAK3、p-JAK3、STAT3、p-STAT3 蛋白表达。针灸可改善寻常型银屑病患者皮损 PASI 评分，降低血清IL-6、TNF-α水平。参考资料 [1]胡怡,武思仙,刘栋,等.中医药调控JAK-STAT通路治疗银屑病的研究进展[J].中成药,2024,46(02):531-536. [2]吴咚咚,曹珣,安月鹏.中医药调控JAK/STAT经典信号通路辨治银屑病的研究进展[J].中国实验方剂学杂志,2023,29(01):258-269. 作者简介：小米虫，药品质量研究工作者，长期致力于药品质量研究及药品分析方法验证工作，现就职于国内某大型药物研发公司，从事药品检验分析及分析方法验证。 END 来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

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