This multicenter, prospective Phase I study is aimed at testing the safety of F8IL10 via i.a. administration once every 4 weeks over 8 weeks in patients with RA who, despite treatment with stable doses (at least 3 months) of DMARDs (conventional, biologic and/or targeted synthetic), present arthritis flare(s) suitable for i.a. injections.

开始日期2023-03-31

申办/合作机构

Philogen SpA

NCT03414788 / Withdrawn临床1期

PHASE 1B, OPEN LABEL STUDY TO CHARACTERIZE THE DISTRIBUTION OF A SINGLE INTRAVENOUS DOSE OF [124I]-IODOBENZOYL (IB)-PF-06687234 WITH CONCURRENT ADMINISTRATION OF NON-RADIOLABELED PF-06687234 AS ASSESSED WITH POSITRON EMISSION TOMOGRAPHY AND COMPUTED TOMOGRAPHY (PET-CT) IMAGING IN MODERATE TO SEVERE ULCERATIVE AND CROHN'S COLITIS SUBJECTS

The purpose of the study is to evaluate the PK, safety and tolerability of PF-06687234 and [124I]IB-PF-06687234 (simultaneously given) in subjects with moderate to severe Ulcerative Colitis or Crohn's Disease. The study used PET-CT scan imaging to assess the distribution of PF-06687234 and [124I]IB-PF-06687234 over 24 and 72 hours in colon (inflamed and non-inflamed), plasma, colon, liver, spleen, kidney and small intestine.

开始日期2020-12-07

申办/合作机构

Pfizer Inc.

NCT03269695 / Terminated临床2期

A PHASE 2A, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY, TOLERABILITY AND PHARMACOKINETICS OF PF-06687234 AS ADD-ON THERAPY TO INFLIXIMAB IN ACTIVE ULCERATIVE COLITIS SUBJECTS WHO ARE NOT IN REMISSION (BUILD UC)

The purpose of this study is to determine if PF-06687234 is effective and safe as add-on therapy to infliximab in subjects with active ulcerative colitis who are not in remission.

开始日期2017-12-20

申办/合作机构

Pfizer Inc.

100 项与 F8-IL10 相关的临床结果

登录后查看更多信息

100 项与 F8-IL10 相关的转化医学

登录后查看更多信息

100 项与 F8-IL10 相关的专利（医药）

登录后查看更多信息

项与 F8-IL10 相关的文献（医药）

2019-12-01·BMC Rheumatology

Fibroblast-like synovial cell production of extra domain A fibronectin associates with inflammation in osteoarthritis

Article

作者: Onuma, Kazuhiro ; Sohn, Dong H ; Kragstrup, Tue W ; Wang, Qian ; Robinson, William H ; Lepus, Christin M ; Sokolove, Jeremy

Abstract:

Background:

The pathophysiology of osteoarthritis (OA) involves wear and tear, and a state of low-grade inflammation. Tissue repair responses include transforming growth factor beta (TGFβ)-induced myofibroblast production of extracellular matrix. Fibronectins are an essential part of the extracellular matrix, and injection of fibronectin fragments into rabbit joints is a previously established animal model of OA. Fibronectin containing the ED-A domain is currently being used as drug delivery target in the development of anti-inflammatory drugs (e.g. Dekavil).

Methods:

In this study, samples of synovial membrane were obtained from patients with knee OA undergoing joint replacement surgery. Immunostaining for ED-A fibronectin and the myofibroblast marker alpha smooth muscle actin (αSMA) was performed on fibroblast-like synovial cells (FLS) and synovial membranes. RAW 264.7 macrophages were incubated with recombinant ED-A fibronectin.

Results:

The staining of ED-A fibronectin in OA FLS was increased by TGFβ but not by TNFα, lipopolysaccharide, or IL-6 (n = 3). ED-A fibronectin co-stained with the myofibroblast marker αSMA in both the OA FLS (n = 3) and in the OA synovial membranes (n = 8). ED-A fibronectin staining was associated with both number of lining layer cells (rho = 0.85 and p = 0.011) and sublining cells (rho = 0.88 and p = 0.007) in the OA synovium (n = 8), and co-distributed with TNFα (n = 5). Recombinant ED-A fibronectin increased the production of TNFα by RAW 264.7 macrophages (n = 3).

Conclusions:

The disease process in OA shares features with the chronic wound healing response. Our findings support utilizing ED-A fibronectin for drug delivery or therapeutic targeting to reduce pro-inflammatory responses in OA.

2019-01-07·Molecular pharmaceutics2区 · 医学

F8-IL10: A New Potential Antirheumatic Drug Evaluated by a PET-Guided Translational Approach

2区 · 医学

Article

作者: Gerrit Jansen ; Guus A M S van Dongen ; Danielle J Vugts ; Conny J van der Laken ; Adriaan A Lammertsma ; Otto S Hoekstra ; Dario Neri ; Carla F M Molthoff ; Marc C Huisman ; Durga M S H Chandrupatla ; René J P Musters ; Stefan T G Bruijnen ; Leonardo Giovanonni

Antibody fragment F8-mediated interleukin 10 (IL10) delivery is a novel treatment for rheumatoid arthritis (RA). F8 binds to the extra-domain-A of fibronectin (ED-A). In this study, in vivo biodistribution and arthritis targeting of radiolabeled F8-IL10 were investigated in RA patients, followed by further animal studies. Therefore, three RA patients (DAS28 > 3.2) received 0.4 mg of 30-74 megabecquerel [¹²⁴I]I-F8-IL10 for PET-CT and blood sampling. In visually identified PET-positive joints, target-to-background was calculated. Healthy mice, rats, and arthritic rats were injected with iodinated F8-IL10 or KSF-IL10 control antibody. Various organs were excised, weighed, and counted for radioactivity. Tissue sections were stained for fibronectin ED-A. In RA patients, [¹²⁴I]I-F8-IL10 was cleared rapidly from the circulation with less than 1% present in blood after 5 min. PET-CT showed targeting in 38 joints (11-15 per patient) and high uptake in the liver and spleen. Mean target-to-background ratios of PET-positive joints were 2.5 ± 1.2, 1.5 times higher for clinically active than clinically silent joints. Biodistribution of radioiodinated F8-IL10 in healthy mice showed no effect of the radioiodination method. [¹²⁴I]I-F8-IL10 joint uptake was also demonstrated in arthritic rats, ∼14-fold higher than that of the control antibody [¹²⁴I]I-KSF-IL10 ( p < 0.001). Interestingly, liver and spleen uptake were twice as high in arthritic than in healthy rats and were related to increased (∼7×) fibronectin ED-A expression in these tissues. In conclusion, [¹²⁴I]I-F8-IL10 uptake was observed in arthritic joints in RA patients holding promise for visualization of inflamed joints by PET-CT imaging and therapeutic targeting. Patient observations and, subsequently, arthritic animal studies pointed to awareness of increased [¹²⁴I]I-F8-IL10 uptake in the liver and spleen associated with moderate systemic inflammation. This translational study demonstrated the value of in vivo biodistribution and PET-CT-guided imaging in development of new and potential antirheumatic drugs'.

2015-09-01·International journal of cardiology2区 · 医学

Targeted delivery of interleukin-10 to chronic cardiac allograft rejection using a human antibody specific to the extra domain A of fibronectin

2区 · 医学

Article

作者: Köse, Nilay ; Jung, Christian ; Ziffels, Barbara ; Franz, Marcus ; Richter, Petra ; Doll, Fabia ; Figulla, Hans R ; Gummert, Jan ; Grün, Katja ; Schubert, Harald ; Berndt, Alexander ; Neri, Dario ; Renner, André

BACKGROUND AND AIMS:

Management of chronic rejection is challenging since there are not sufficient preventive or therapeutic strategies. The rejection process leads to overexpression of ED-A(+) fibronectin (ED-A(+) Fn). The human antibody F8, specific to ED-A(+) Fn, may serve as a vehicle for targeted delivery of bioactive payloads, e.g. interleukin 10 (IL-10). The aim of this study was to investigate the therapeutic effects of the fusion protein F8-interleukin-10 (F8-IL10) in the process of chronic rejection development.

METHODS:

A heterotopic rat heart transplantation model was used to induce chronic rejection. For therapeutic interventions, the immunocytokines F8-humanIL10 (DEKAVIL), F8-ratIL10 as well as KSF-humanIL10 (irrelevant antigen-specificity) were used. Treatment was performed weekly for 10 weeks starting at day 7 after transplantation (1mg/animal).

RESULTS:

In the cardiac allografts, treatment with F8-huIL10 or F8-ratIL10 was associated with increased heart weights, a higher grade of chronic rejection, increased CIF, higher protein expression levels of alpha-smooth muscle actin (α-SMA), an augmented infiltration with inflammatory cells (CD4+, CD8+ and CD68+ cells) and higher serum levels of brain natriuretic peptide (BNP) compared to the control groups.

CONCLUSIONS:

All observed treatment effects are transplantation-specific since the F8 antibody is specific to ED-A(+) Fn that is not expressed in healthy hearts. A clear targeting effect of F8-huIL10 as well as F8-ratIL10 could be proven. Against that background, a further study is needed to address the question, if F8-IL10 treatment is capable to reduce CAV and CIF starting at a time point when chronic rejection has fully developed (therapeutic approach).

项与 F8-IL10 相关的新闻（医药）

2023-12-23

·生物制品圈

单链抗体的研究进展及其在疾病治疗中的应用

中文摘要单链抗体（single chain fragment variable，scFv）是通过基因工程改造的重组抗体，保留了抗体的靶向性，同时因为体积较小而获得了完整抗体不具有的特性，例如渗透性好、易扩散、免疫原性弱、体内存留时间短以及容易表达等。这些特性使得scFv可以作为一种十分理想的靶向性分子应用于疾病的诊断和治疗。scFv可以与荧光蛋白融合发挥疾病诊断的作用；也可以与化学毒素相连形成免疫毒素用于癌症的治疗；scFv连接到T细胞上，则构建成嵌合抗原受体T细胞，是十分具有前景的癌症治疗技术。此文综述了scFv的相关制备技术及相关药物在临床试验中的应用。正文抗体是浆细胞在体液免疫中所产生的免疫球蛋白，天然的抗体由4条肽链构成，2条重链2条轻链，共同构成Y形的结构，见图1。完整的抗体包括2个结构域：抗原结合片段（fragment of anigen binding，Fab）和可结晶片段（fragment crystallizable，Fc）。Fab中的抗体可变区包括重链可变区（VH）和轻链可变区（VL）能特异性结合抗原；Fc则帮助维持抗体的正常结构，并且在抗体依赖性细胞介导的细胞毒作用、补体依赖的细胞毒性、抗体介导的吞噬作用等免疫过程中发挥重要作用。完整抗体虽然在医疗领域有很高的利用价值，但相对分子质量较大、不易扩散、表达成本高，需要进行改造以赋予多样化的功能和特性。单链抗体（single chain fragment variable，scFv）是一种十分重要的重组抗体，仅包含VH和VL。scFv中的VH和VL通过15~25个氨基酸的linker连接成链状，linker通常富含亲水性氨基酸，如甘氨酸、丝氨酸等，组成类似（GGGGS）n的结构，使得肽链具有足够的灵活性。linker的氨基酸组成和氨基酸数目与scFv的活性和稳定性相关，如果linker含有疏水性氨基酸，可能使得VH和VL相互缠绕，影响其活性；linker长度太短则会使scFv容易形成二聚体的结构。在使用相同linker序列的前提下，VH和VL在肽链中N端或C端的相对位置也会对scFv的结合特性有一定的影响。scFv虽然只有1条链，但包含了抗体与抗原结合的关键区域，保留了抗原结合能力，同时也获得了相对分子质量小、易扩散、免疫原性弱、体内停留时间短、容易表达等特性。这些特点使得其被广泛应用于疾病治疗和诊断等相关领域，在嵌合抗原受体（chimeric antigen receptor，CAR）T 细胞技术、流式细胞术、免疫组织化学、靶向性抗肿瘤药物等方面都发挥了重要作用。本文主要介绍scFv库的筛选、scFv在不同系统中的表达以及在治疗和诊断中的应用。1scFv的展示和表达获得scFv可以通过对已有序列进行重组构建，也可以通过构建抗体展示系统对不同类型的scFv进行大规模地展示和筛选，以获得具有良好结合性能的scFv。常用的抗体展示技术有噬菌体抗体展示技术、核糖体展示技术、细菌抗体展示技术等，现在广泛使用的主要是噬菌体抗体展示技术和核糖体展示技术，本文以这两项技术为例进行阐述。1.1scFv的展示技术1.1.1 噬菌体抗体展示技术丝状噬菌体展示系统是目前最成熟并广泛使用的噬菌体展示系统，丝状噬菌体为单链DNA病毒，基因组的大小在6 400 bp左右，可以插入并表达10个不同的蛋白质。与插入基因表达有关的基因为表面蛋白pⅢ基因和pⅧ基因，使用pⅢ可以插入较大的片段，而pⅧ适合较小的插入片段。噬菌体抗体展示技术通过基因工程方法从B淋巴细胞库中扩增获得抗体VH和VL文库，进而通过PCR获得天然或免疫文库，或者对已有的抗体序列进行关键区域随机突变，获得突变文库和合成文库；然后把克隆的scFv文库基因序列插入到M13噬菌体质粒中，与噬菌体基因组中的pⅢ或pⅧ基因融合，在噬菌体外壳表达scFv与pⅢ或pⅧ的融合蛋白。这样得到的噬菌体质粒中有抗体基因的存在，同时又在噬菌体的表面有scFv的表达，从而做到了基因型与表现型的统一。再利用抗原-抗体特异性结合的原理，通过适当的淘选方法，例如结合-洗脱-扩增-结合依次循环进行筛选，可以得到与抗原具有较强结合能力的抗体序列；并可以用测序的方法在后续进行快速鉴定。VH和VL随机配对重组以及多轮淘选过程，在一定程度上模仿了动物免疫系统中的抗体亲和力成熟过程，从众多的scFv基因序列中筛选出具有抗原结合能力的少量序列。在筛选的过程中，带有高亲和力抗体片段的噬菌体会与抗原紧密结合，而无法结合的抗体片段则被冲洗掉，从而得到了高亲和力噬菌体-抗体复合物。再通过把所得到的噬菌体-抗体复合物侵染大肠埃希菌，便可获得大量的噬菌体；通过基因工程技术使抗体基因以分泌的方式表达，则可以获得可溶性抗体片段。但是，由于这种淘选过程是在体外进行的，无法完全模仿体内抗体的阴性筛选和阳性筛选的过程，因此最后得到的抗体序列可能存在非特异性结合、或亲和力较低的现象。1.1.2 核糖体展示技术核糖体展示技术的原理是通过去除mRNA 3'的终止密码子，使得翻译结束后肽链和核糖体无法从mRNA上释放，从而形成三元复合物多肽-核糖体-mRNA；通过固相筛选或液相筛选的方法（ELISA、磁珠法等)，利用目标抗原筛选得到抗原结合能力较高的三元复合物，再通过逆转录PCR技术重新构建DNA模板，进行多轮筛选以富集与抗原具有较强结合能力的scFv。核糖体展示技术一般包括3个步骤：展示模板的构建、体外转录和翻译、亲和筛选。完整的展示模板通常由4个部分组成：5'非编码区、目的基因、间隔序列和3'非编码区，其中5'非编码区中包含了T7启动子序列和核糖体结合位点序列；间隔序列的作用是scFv与核糖体具有一定的距离，防止核糖体干扰scFv的折叠；3'端的非编码区则剔除了终止密码子，防止mRNA、蛋白质和核糖体相互分离，帮助形成多肽-核糖体-mRNA复合物。核糖体展示技术有很多优势。由于完全在体外开展，避免了向生物细胞内转化的要求，因此克服了体内筛选技术对库容的限制，其库容量可以达到1014，比噬菌体展示系统的库容量更大。而且由于完全在体外进行，因此核糖体展示技术还可以筛选一些对细胞有毒性的分子。更为重要的是，在PCR中可以使用易错PCR技术来实现体外的亲和力成熟和抗体进化。但这种展示系统的缺陷也比较明显，mRNA易降解、多肽-核糖体-mRNA复合物的稳定性也较差，显著影响了展示系统的正常运行;另外，大分子蛋白质的展示效率低也是亟待解决的问题。1.2scFv表达系统对筛选得到的高亲和力scFv进行活性验证、大规模生产等，需要使用细菌或细胞表达系统对scFv进行表达。细菌、酵母菌和昆虫、哺乳动物、植物细胞等都可以用于在体外进行蛋白质的大规模表达，而不同的表达系统有不同的特点，适合于不同种类的蛋白或抗体片段。原核生物表达系统是在scFv表达过程中最常用到的表达系统，具有生长速度快、遗传背景清晰、产量高、成本低等特点。由于scFv本身的结构比较简单，不需要很复杂的翻译后修饰过程，因此原核细胞比较适合scFv的快速表达及筛选；在使用原核生物细胞进行表达的过程中可能需要克服包涵体的出现，可以通过添加信号肽等优化方式，使scFv可溶性表达，防止合成的scFv形成包涵体，有利于后期的蛋白纯化。而相对来说，真核生物细胞能够完成更加复杂的蛋白质折叠和翻译后修饰，但需要更高的成本。真核生物表达系统主要有酵母菌网、植物、昆虫、哺乳动物细胞等种类。总体而言，由于scFv的结构相对简单、几乎不需要翻译后修饰，因此主要使用原核细胞进行表达。2scFv在疾病治疗中的应用随着scFv技术逐步发展成熟，它的应用已经遍布了很多领域，下文选择在临床试验期间表现较好的几种药物，对近年来一些scFv在疾病治疗方面的应用进行总结。2.1自身免疫病的治疗当下用于自身免疫病的治疗药物大致分为生物药物和非生物药物，其中最普遍使用的是非生物药物，例如甲氨蝶呤、皮质类固醇和柳氮磺吡啶等，但是这些药物由于没有靶向性，对正常组织的毒性较大，会导致患者容易发生感染和毒素累积的危险。生物类药物主要包括单克隆抗体（单抗）和抗体偶联药物，它们相比于非生物类药物最显著的优势是高度的靶点特异性、低不良反应和低毒性。生物类药物正在迅速发展为自身免疫病药物的主要类型，其中多种scFv融合蛋白在临床上取得良好的效果。在临床试验阶段表现较好的有Dekavil和 Brolucizumab。Dekavil是一种抗体-细胞因子融合蛋白，由靶向纤连蛋白胞外域A的全人源scFv F8和抑制炎症的细胞因子IL-10组成，用于治疗类风湿关节炎。纤连蛋白的胞外域A在关节炎部位高水平表达，在健康组织中几乎不表达，利用scFv的靶向性可将活性物质IL-10在炎症部位富集发挥抗炎作用。临床试验表明，IL-10与scFv F8的结合比单独的IL-10效果更好，Dekavil目前已经进入Ⅱ期临床试验，在类风湿关节炎的治疗中具有安全性和一定的有效性。Brolucizumab是一种靶向血管内皮生长因子（vascular endothelial growth factor，VEGF）的人源化scFv，于2019年获FDA批准用于治疗年龄相关性黄斑变性（age-related macular degeneration，AMD）。它靶向结合VEGF，抑制VEGF与其受体结合，进而抑制脉络膜层新血管的产生，从而防止视网膜液泄露到视网膜层。在2项Ⅲ期临床研究（HAWK、HARRIER）中，Brolucizumab可以显著并长期恢复AMD患者的视力；对不同类型患者的个性化治疗方案，最终均能达到长期的视力恢复。2.2肿瘤靶向治疗scFv与其他分子形成的复合物，例如scFv-细胞因子融合蛋白、scFv-毒素复合物、scFv-细胞因子受体融合蛋白等，在肿瘤治疗方面有多种应用。2.2.1 抗体-细胞因子融合蛋白 scFv-细胞因子融合蛋白中scFv部分的靶向性十分重要，scFv的靶点应是在肿瘤组织周围大量表达、而在正常组织不表达的抗原。现在受关注的靶点主要有人表皮生长因子受体2/3、连接蛋白4、人滋养层细胞表面抗原2、亮氨酸-异亮氨酸-缬氨酸结合蛋白1家族、癌胚抗原相关细胞黏附分子、间皮素、肝细胞生长因子受体、叶酸受体α、CD19、CD22等；研究较多的细胞因子有IL-2、IL-12和TNF等。目前scFv-细胞因子融合蛋白研究多处于实验室阶段，进入临床试验的很少，在小鼠模型中的肿瘤治疗效果较好。进入临床试验的产品大多使用IL-2、TNF或IL-12等细胞因子，其中Fibromun是基于TNF的融合蛋白，包括L19 scFv和纤维连接蛋白B结构域，以同源三聚体的形式发挥作用。Fibromun表现出显著的肿瘤靶向性和极强的抗肿瘤效果，在Ⅲ期临床试验中发现其与L19-IL-2（Darleukin）联用可以对ⅢB/C期的黑色素瘤发挥很好的治疗效果。2.2.2 免疫毒素将scFv与毒素相连接成为免疫毒素是另一种十分普遍的肿瘤靶向治疗策略，其中最常使用的毒素就是白喉毒素（diphtheria toxin，DT）。DT是棒状杆菌表达的一种外毒素，可以进入细胞质抑制蛋白表达，从而对细胞进行杀伤。这里列举2种比较有前景的基于scFv和DT的免疫毒素，DT2219和DT-AntiCCR4。DT2219同时靶向于CD19和CD22。CD19是一种表达于所有类型的B细胞表面的糖蛋白，CD22则主要表达于前体B细胞和B细胞，它们都同样广泛表达于B细胞白血病和淋巴瘤中。DT2219同时靶向这2个靶点，可能在一定程度上增加了不良反应的风险，但也提高了对B细胞白血病和淋巴瘤的应答，在临床试验中表现良好。另一研究则单独使用了靶向CD19的scFv与DT融合，在动物实验中也有较好的效果，同时没有明显的毒性，更多研究结果尚未披露。DT-AntiCCR4靶向C-C趋化因子受体4（C-C chemokine receptor type 4，CCR4）， CCR4 主要表达于T细胞相关的肿瘤，如外周T细胞淋巴瘤、急性T淋巴母细胞白血病、皮肤T细胞淋巴瘤等细胞表面。在这种免疫毒素的研究过程中，尝试了很多融合蛋白的形式，包括DT390-scFv单体、DT390-biScFv二聚体和DT390-Fold-back双特异性抗体的形式。在体内实验中，对小鼠移植急性淋巴祖细胞白血病细胞系（CCRF-CEM）给药结果表明，二聚体和双特异性抗体融合形式均对CCRF-CEM细胞系起到了显著的抑制作用，存活率比对照组小鼠明显提高。但是由于CCR4也表达于其他细胞群体如CD4+、CD8+ T细胞，因此DT-AntiCCR4在这方面的影响还有待进一步研究。2.2.3 基于CAR-T细胞的肿瘤治疗方法 CAR-T细胞技术是一种新兴的基于scFv的肿瘤治疗方法。在CAR-T细胞系统中的CAR部分表达于T细胞膜上，主要包括1个scFv、1个跨膜结构域和1个胞内结构域，结构如图2所示。其中scFv用于特异性识别抗原，跨膜结构域和胞内结构域部分帮助跨膜传递信号以激活T细胞。T细胞一旦被激活，则可以通过释放穿孔素和颗粒酶杀伤靶细胞。这样的T细胞激活方式与通过T细胞受体激活T细胞有着相同的效果，但利用不相关的CD8+ T细胞杀伤癌细胞；并且使用scFv与抗原特异性结合的方式，绕过了T细胞受体在识别抗原过程中的MHC限制性，从而大大提高了有特异性杀伤能力的CD8+ T细胞数量，对癌细胞的杀伤能力显著提升。CAR-T细胞疗法正在被广泛地研究和使用，靶向的抗原十分多样，其中主要的靶点是CD19、CD20、CD22、CD33等；针对的疾病类型也非常广泛，在淋巴瘤和实体瘤方面的研究都有很多探索。经典CAR-T细胞具有固定的结构，一种CAR-T细胞只能靶向到一种抗原表位上，这种设计限制了CAR-T细胞在临床应用的可能性，大大增加了治疗成本。通用CAR-T细胞在设计时把抗原识别区域与信号传导区域分开设计，使用一个可转换组件相连接，在需要改变靶点的时候只改变抗原识别部位即scFv，而无需重新设计和合成整个CAR-T细胞。通用CAR-T细胞不仅有利于靶点的转换，而且也可以通过调节scFv靶向性组件的浓度，来稀释或增强CAR-T细胞系统的作用强度，从而有效地控制CAR-T细胞可能出现的不良反应。通用CAR-T细胞的这些特点使得它在临床应用中有更大的潜力，更加扩大了 ScFv作为肿瘤治疗相关蛋白的使用广度，同时也降低了医疗成本。3展望由于相对分子质量较小，scFv获得了很多完整抗体不具有的特性，如易扩散、免疫原性弱、体内停留时间短、易表达等。这些特性使得scFv具有特殊的用途，比如可以用于构建免疫毒素、抗体-细胞因子融合蛋白、双特异性抗体、CAR-T细胞等，从而靶向到特异性位点发挥作用。随着抗体库筛选技术和蛋白表达技术的日趋发展和成熟，scFv将在肿瘤治疗、病毒检测与防控及药物输送等领域取得突破性进展。scFv有望改进肿瘤靶向治疗，提高疫苗研发效率，并实现精确药物递送，其广泛应用将为人类健康带来福音。作者陈团结1 综述陈哲文2 审校1上海生物制品研究所有限责任公司第一研究室，上海 200051；2上海生物制品研究所有限责任公司，上海 201403通信作者：陈哲文，Email：13917843916@163.com引用本文：陈团结, 陈哲文. 单链抗体的研究进展及其在疾病治疗中的应用 [J]. 国际生物制品学杂志, 2023, 46(5): 283-288. DOI: 10.3760/cma.j.cn311962-20230219-00017识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

细胞疗法免疫疗法

2023-01-09

·PRNewswire

Rheumatoid Arthritis Market is Expected to Showcase Significant Growth in the 7MM at a Minimal CAGR of 1.9% During the Study Period (2019-2032), Predicts DelveInsight

The dynamics of the rheumatoid arthritis market are anticipated to change in the coming years owing to the increasing awareness and expected increase in investment in the R&D activities. Companies like GlaxoSmithKline [Otilimab (MOR103/GSK3196165)], Taisho Pharmaceutical [Ozoralizumab (TS-152)], Aclaris Therapeutics [Zunsemetinib (ATI-450)], Abivax [ABX464], and others with their key candidates are in the late clinical and filing stage. LAS VEGAS, Jan. 9, 2023 /PRNewswire/ -- DelveInsight's Rheumatoid Arthritis Market Insights report includes a comprehensive understanding of current treatment practices, rheumatoid arthritis emerging drugs, market share of individual therapies, and current and forecasted market size from 2019 to 2032, segmented into the 7MM [the United States, EU4 (Germany, France, Italy, and Spain), the United Kingdom, and Japan]. Key Takeaways from the Rheumatoid Arthritis Market Report As per DelveInsight analysis, the rheumatoid arthritis market size in the 7MM was approximately USD 27 billion in 2021. According to the assessment done by DelveInsight, the estimated total rheumatoid arthritis prevalent population in the 7MM was approximately 4. 7 million in 2021. Leading rheumatoid arthritis companies such as Taisho Pharmaceuticals, R-Pharm, GlaxoSmithKline, Aclaris Therapeutics, Pfizer, Abivax, Bristol Myers Squibb, Oscotec/Genosco, Mesoblast, Pfizer Akros Pharma/Japan Tobacco, Abbvie, Horizon Therapeutics, Eli Lilly and Company, Taiho Pharmaceutical, Gilead Sciences, Kiniksa Pharmaceuticals, Istesso, SynAct Pharma, Cyxone, and others are developing novel rheumatoid arthritis drugs that can be available in the rheumatoid arthritis market in the coming years. The promising rheumatoid arthritis therapies in the pipeline include Ozoralizumab (TS-152), Artlegia (Olokizumab), Otilimab (GSK3196165/MOR103), Zunsemetinib (ATI-450), Ritlecitinib (PF-06651600), ABX464, Branebrutinib, Cevidoplenib (SKI-O-703), MPC-300-IV, PF-06650833, JTE -051, ABBV-154, TAS5315, MBS2320, AMT-101, AP1189, Rabeximod (Rob 803), and others. In June 2022, Cyxone received a response from a Type B Pre-IND meeting with the US FDA. The response from the FDA facilitates Cyxone to continue planning the Phase IIb study with Rabeximod in RA. In December 2021, Taisho Pharmaceuticals presented the interim results from a 24-week administration in Phase II/III clinical trial (OHZORA study) of ozoralizumab in adult patients with RA at the annual meeting of the Japanese Society for Clinical Rheumatology and Related Research. Discover which therapies are expected to grab the major rheumatoid arthritis market share @ Rheumatoid Arthritis Market Report Rheumatoid Arthritis Overview Rheumatoid arthritis is a type of autoimmune disease. It happens when our immune system, which is supposed to defend us, malfunctions and starts attacking our own tissues. It causes inflammation in the joint lining (the synovium). As a result, joints may become red, warm, swollen, and painful, which are all symptoms of rheumatoid arthritis. The precise causes of rheumatoid arthritis are still unknown. Because the early signs and symptoms of rheumatoid arthritis are similar to those of many other diseases, it can be difficult to detect in its early stages. There is no single blood test or physical finding that can confirm the diagnosis of rheumatoid arthritis. There is no known cure for rheumatoid arthritis. However, clinical trials of rheumatoid arthritis show that remission of symptoms is more common when rheumatoid arthritis treatment with disease-modifying antirheumatic medicines begins early (DMARDs). Rheumatoid Arthritis Epidemiology Segmentation DelveInsight estimates that there were approximately 4.7 million prevalent cases of rheumatoid arthritis in the 7MM in 2021. Among the EU4 and the UK countries, Germany accounted for the highest number of rheumatoid arthritis cases, whereas France accounted for the lowest cases in 2021 The rheumatoid arthritis market report proffers epidemiological analysis for the study period 2019–2032 in the 7MM segmented into: Total Prevalent Cases Total Diagnosed Prevalent Cases Gender-specific Prevalent Cases Age-specific Prevalent Cases Severity-specific Prevalent Cases Patients on Targeted Therapies Line-Wise Treated Cases Download the report to understand which factors are driving rheumatoid arthritis epidemiology trends @ Rheumatoid Arthritis Epidemiological Insights Rheumatoid Arthritis Treatment Market Over the last few years, there has been a dramatic improvement in rheumatoid arthritis outcomes as a direct result of paradigm shifts in rheumatoid arthritis treatment. At the moment, the main rheumatoid arthritis treatment options are Medicine (for long-term relief of symptoms and slowing the progression of the condition), Supportive treatments (including physiotherapy and occupational therapy, to help keep the patient mobile and manage any problems related to daily activities), and Surgery (to correct any joint problems that develop over a period of time). Nonsteroidal anti-inflammatory drugs (NSAIDs) are typically used only for symptomatic treatment until a rheumatoid arthritis diagnosis is established because they reduce pain and stiffness in patients but have no effect on disease progression. Moreover, disease-modifying antirheumatic drugs (DMARDs) are used to target inflammation and prevent further joint damage and disease progression. DMARDs are a class of drugs that have been shown to affect the underlying cause of rheumatoid arthritis by reducing immune system overactivity, thereby alleviating pain, swelling, and stiffness and preventing joint changes. DMARDs can be prescribed singly or in combination as an initial part of treatment. Methotrexate is the first-line DMARD agent for the majority of rheumatoid arthritis patients. It has a relatively quick onset of action at therapeutic doses (6-8 weeks), good efficacy, a low toxicity profile, is easy to administer, and is relatively inexpensive. To know more about rheumatoid arthritis guidelines, visit @ Rheumatoid Arthritis Management Rheumatoid Arthritis Pipeline Therapies and Key Companies Artlegia (Olokizumab): R-Pharm TS-152 (Ozoralizumab): Taisho Pharmaceuticals Otilimab (GSK3196165/MOR103): GlaxoSmithKline ATI-450 (Zunsemetinib/CDD-450): Aclaris Therapeutics Branebrutinib: Bristol Myers Squibb LY3462817: Eli Lilly and Company TAS5315: Taiho Pharmaceutical Rabeximod (Rob 803): Cyxone GS-5718: Gilead Sciences KPL-404: Kiniksa Pharmaceuticals MBS2320: Istesso AMT-101: Applied Molecular Transport Dazodalibep (HZN-4920): Horizon Therapeutics Cevidoplenib (SKI-O-703): Genosco/Oscotec HB-AdMSCs: Hope Biosciences ABX464: Abivax MPC-300-IV: Mesoblast PF-06650833: Pfizer JTE 051: Akros Pharma/Japan Tobacco Dekavil (F8IL10): Pfizer/Philogen ABBV-154: AbbVie PF-06651600 (Ritlecitinib): Pfizer AP1189: SynAct Pharma Learn more about the FDA-approved drugs for rheumatoid arthritis @ Drugs for Rheumatoid Arthritis Treatment Rheumatoid Arthritis Market Dynamics The dynamics of the rheumatoid arthritis market is anticipated to change in the future due to the increasing awareness and expected increase in investment in the R&D activities by the leading companies working in the rheumatoid arthritis market space. Moreover, current therapies, such as biological DMARDs, have shown promising results in treating rheumatoid arthritis patients, and market penetration is expected to increase in the future, driving rheumatoid arthritis market growth. Furthermore, there is still a high demand for therapies with a similar efficacy profile to current therapies but a better safety profile and a more patient-friendly RoA. Oral classes, such as JAKi and the upcoming BTKi, are expected to contribute to the rheumatoid arthritis market growth due to patient-friendly RoA. However, several factors are likely to hamper the rheumatoid arthritis market growth. The rheumatoid arthritis market is highly competitive, and new entrants are expected to face some resistance and low uptake because anti-TNFs currently dominate the rheumatoid arthritis market, and the entry of biosimilars will pose significant challenges to new and upcoming treatment options in the rheumatoid arthritis market. In addition, the entry of biosimilars has already begun in the US and EU (i.e., Remicade biosimilars), and as a result, sales value has started to decline. The impact will be more pronounced when biosimilars/ generics of some blockbuster drugs, such as Humira (i.e., 2023 in the US), Xeljanz (i.e., 2025 in the US), will enter the rheumatoid arthritis market, and this will significantly impact the growth of the rheumatoid arthritis market. Scope of the Rheumatoid Arthritis Market Report Therapeutic Assessment: Rheumatoid Arthritis current marketed and emerging therapies Rheumatoid Arthritis Market Dynamics: Rheumatoid Arthritis market drivers and barriers Competitive Intelligence Analysis: SWOT analysis, PESTLE analysis, Porter's five forces, BCG Matrix, Market entry strategies Unmet Needs, KOL's views, Analyst's views, Rheumatoid Arthritis Market Access and Reimbursement Discover more about rheumatoid arthritis drugs in development @ Rheumatoid Arthritis Clinical Trials Table of Contents Related Reports Rheumatoid Arthritis Epidemiology Forecast Rheumatoid Arthritis Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted rheumatoid arthritis epidemiology in the 7MM, i.e., the United States, EU4 (Germany, France, Italy, and Spain), the United Kingdom, and Japan. Juvenile Rheumatoid Arthritis Pipeline Juvenile Rheumatoid Arthritis Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products and the key juvenile rheumatoid arthritis companies, including Novartis, AbbVie, Eli Lilly and Company, Sanofi, among others. Juvenile Rheumatoid Arthritis Market Juvenile Rheumatoid Arthritis Market Insights, Epidemiology, and Market Forecast – 2032 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key juvenile rheumatoid arthritis companies, including Novartis, AbbVie, Eli Lilly and Company, Sanofi, among others. Psoriatic Arthritis Pipeline Psoriatic Arthritis Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key psoriatic arthritis companies, including Mylan, Celltrion, Pfizer, Amgen, among others. Psoriatic Arthritis Market Psoriatic Arthritis Market Insights, Epidemiology, and Market Forecast – 2032 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key psoriatic arthritis companies, including Mylan, Celltrion, Pfizer, Amgen, among others. Other Trending Reports Tay-sachs Disease Or Gm2 Gangliosidosis Market | Onycholysis Market | Diagnostic Imaging Equipment Market | Chemotherapy-induced Peripheral Neuropathy Market | Global Electrophysiology Devices Market | Anaphylaxis Market | Atherectomy Devices Market | Helicobacter Pylori Infections Market | Ophthalmic Imaging Equipment Market | Androgenetic Alopecia Market | Allergic Rhinitis Market | Chronic Inflammatory Demyelinating Polyneuropathy Market | Chronic Inflammtory Demyelinating Polyneuropathy Market | Colorectal Cancer Crc Market | Opioid Induced Constipation Market | Vertigo Market | Bone Anchored Hearing Systems Market | Wound Closure Devices Market | Hip Replacement Devices Market | Hemodynamic Monitoring Systems Market | Egfr Non-small Cell Lung Cancer Market | Helicobacter Pylori Infection Market | Hyperkalemia Market | Polycythemia Market Neurostimulation Devices Market | Carpal Tunnel Syndrome Market | Ventilator Market | Cerebral Aneurysm Market | Alpha Antitrypsin Market | Binge Eating Disorder Market | Bunion Market | Concussions Market Size | Exocrine Pancreatic Insufficiency Market | Healthcare Due Diligence Services | Minimal Residual Disease Market Related Healthcare Blogs Rheumatoid Arthritis Emerging Drugs Knee Osteoarthritis Pipeline Rheumatoid Arthritis Market Scenario Juvenile Idiopathic Arthritis Therapy Market Related Healthcare Services Healthcare Business Consulting Healthcare Competitive Intelligence Services Healthcare Asset Prioritization Services About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Connect with us on LinkedIn |Facebook|Twitter Additionally, get in touch with our business executive to explore @ Healthcare Due Diligence Services Contact Us Shruti Thakur [email protected] +1(919)321-6187 Logo: SOURCE DelveInsight Business Research, LLP

临床结果

2022-11-28

·药研网

IL-10：荆棘丛生之路

IL-10自1989年首次被发现，针对它的学术研究已进行了三十余年，但时至今日，它在药物研发领域仍然是个“冷门”。01靶点概述白介素10(IL-10)最初被描述为Th2细胞细胞因子。包括IL-19、IL-20、IL-22、IL-24、IL-26、IL-28A、IL-28B和IL-29等，这些与IL-10具有相似蛋白质结构和受体复合物的细胞因子也被称为IL-10家族细胞因子。IL-10是一种现在被认为是复杂的多效的细胞因子，能够影响上皮功能并参与过敏和感染等炎症疾病，具有重要的免疫调节功能。其主要由抗原呈递细胞分泌，如活化的T细胞、单核细胞、B细胞和巨噬细胞。在生物功能形式中，IL-10以同源二聚体的形式存在，与四聚体异二聚体IL-10R结合并诱导下游信号转导。功能性IL-10R复合体是由两个配体结合亚基IL-10Rα（IL-10R1）和两个辅助信号亚基IL-10Rβ（IL-10R2）组成的四聚体。[1]02信号通路IL-10与IL-10Rα胞外结构域的结合激活了受体相关的JAK1和TYK2的磷酸化，然后IL-10Rα链胞内结构域的特异性酪氨酸残基Y446和Y496被磷酸化，这些酪氨酸残基(及其侧肽序列)就会成为潜在转录因子STAT3的临时停靠点。STAT3通过其SH2结构域与这些位点结合，继而被受体相关的JAKs酪氨酸磷酸化，继而STAT3二聚化入核，激活核内基因的转录翻译，从而增加了抗凋亡和细胞周期进展基因的转录。IL-10信号通路示意图[2]此外，IL-10还可以激活PI3K及其下游底物p70S6K和Akt/PKB。尽管IL-10的抗炎作用不是通过PI3K介导的，但IL-10促进星形胶质细胞存活或诱导肥大细胞增殖的能力取决于PI3K的激活。IL-10还会干扰LPS及其受体TLR4的下游信号p38/MAPK通路，从而抑制肿瘤坏死因子的翻译通路（TNF-mRNA）。在一些研究中，IL-10促进癌细胞生长和存活，包括非霍奇金淋巴瘤、伯基特淋巴瘤和非小细胞肺癌，IL-10过表达与SLE，结核病相关，而炎症性肠病、银屑病、哮喘、类风湿性关节炎等疾病与IL-10缺乏相关。03竞争格局2018年，礼来斥资16亿美元收购ARMO Biosciences，获得其下IL-10项目pegilodecakin。2019年，其治疗胰腺癌的III期临床因未达主要终点而宣告失败，之后，其治疗肺癌的两个II期临床也终止，一番挣扎之后，这款名噪一时的候选药消失得悄无声息。同年，Biotest AG宣布其人源化IL-10单抗BT-063治疗系统性红斑狼疮的2期临床试验结果达主要终点，BT-063在自免疫疾病治疗领域大有可为。然而至今，官网管线中已不见其身影。此外，包括默沙东的MK-1966、Y-Biologics的YBL010和Cytonus Therapeutics的CA-IL10等十几条管线均已终止开发，不了了之。时至今日，IL-10赛道中多家公司或机构纷纷进入，又纷纷离开，仍然在这条赛道上奔跑的选手已所剩无几。AMT-101是一种新型的、具有消化道选择性的的口服重组生物融合蛋白——人白细胞介素10（hIL-10），主要用于治疗炎症性肠病和系统性炎症适应症。该药物采用AMT的专有平台设计，旨在利用肠道内自然生物运输机制的力量，使其能够穿过肠道上皮屏障，直接与肠道组织中丰富的免疫环境中的细胞相互作用。今年7月公布的治疗中度至重度溃疡性结肠炎（UC）的2期顶线结果显示，对于主要终点来说，AMT-101联合阿达木单抗治疗组的临床缓解率（31.8%）与对照组安慰剂联合阿达木单抗治疗组（临床缓解率33.3%）相比，并没有表现出更好的疗效优势。但是在UC病程＜5年的患者中，AMT-101联合治疗的临床缓解率为43.8%，对照组15.4%，疗效显著。Dekavil (F8IL10)由F8抗体与IL10融合组成，它对纤连蛋白的EDA结构域具有特异性，能选择性地定位在各种炎症的炎症组织中。XT-150是一种局部注射的质粒DNA基因疗法，表达IL-10v（一种IL-10的专有改良变体），以解决病理性炎症和疼痛。XT-150与目前的标准治疗相比，大大增加了其效果的持续时间。小结：IL-10自发现至今已30多年，在这条布满荆棘的道路上，有人倒下，也有人在艰难前行，致敬这些荆棘途中形单影只的孤勇者，也期待这些药物后续会有更好的进展。扫码查询现货细胞系参考：1. doi:10.1111/febs.162072.https://www.thermofisher.cn/cn/zh/home/life-science/antibodies/antibodies-learning-center/antibodies-resource-library/cell-signaling-pathways/il-10-pathway.html3. doi: 10.3389/fimmu.2022.9479834. doi: 10.1084/jem.201904185. doi: 10.1080/2162402X.2021.20035336. 各企业官网往期推荐PROTAC全球布局一览Fierce Biotech丨2022年医药企业裁员追踪盘点国产PD-1销售盘点点击下方“药研网”，关注更多精彩内容

临床2期并购信使RNA临床结果临床1期

100 项与 F8-IL10 相关的药物交易

登录后查看更多信息

研发状态

适应症	最高研发状态	国家/地区	公司
类风湿关节炎	临床2期	-	Pfizer Inc. 更多
炎症性肠病	临床2期	-	Pfizer Inc. 更多
炎症	终止	美国更多	Pfizer Inc. 更多
克罗恩病	终止	美国更多	Pfizer Inc. 更多
溃疡性结肠炎	终止	美国更多	Pfizer Inc. 更多

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03269695 (CTgov)	临床2期	溃疡性结肠炎	20	Placebo+Infliximab (Placebo + Infliximab)	齋範築壓範築鏇繭顧鏇(壓鏇觸窪願夢遞鬱製鑰): Treatment difference = 1.8 (95% CI, -41.0 ~ 47.2), P-Value = 1.0000 更多	-	2021-12-28
NCT03269695 (CTgov)	临床2期	溃疡性结肠炎	20	Infliximab+PF-06687234 (PF-06687234 20 mg + Infliximab)		-	2021-12-28
NCT02076659 (EULAR2018) 人工标引	临床2期	类风湿关节炎	-	F8-IL10	襯觸顧積艱網積築廠製(窪願構觸蓋獵衊範鹹醖) = 選製餘廠網鏇鹽鏇鑰繭壓網獵鏇醖鹹積鹽顧蓋 (觸衊積襯構壓獵觸願選 )	积极	2018-06-15
phase Ib and phase II (EULAR2016)	临床1/2期	类风湿关节炎 anti-TNFα treatment	-	Dekavil 6 μg/kg	餘鹽淵簾網積繭遞廠鏇(觸衊顧鬱餘簾繭積製衊) = 觸糧鑰窪廠觸鏇廠築齋簾糧廠艱遞窪齋夢網淵 (夢鏇顧鏇壓範簾願衊獵 ) 更多	积极	2016-06-08