更新于：2024-05-01

plectin

更新于：2024-05-01

基本信息

别名

EBS1、HD1、Hemidesmosomal protein 1

+ [6]

简介

Interlinks intermediate filaments with microtubules and microfilaments and anchors intermediate filaments to desmosomes or hemidesmosomes. Could also bind muscle proteins such as actin to membrane complexes in muscle. May be involved not only in the filaments network, but also in the regulation of their dynamics. Structural component of muscle. Isoform 9 plays a major role in the maintenance of myofiber integrity.

关联

项与 plectin 相关的药物

ZB-131

靶点

plectin

作用机制

plectin抑制剂

在研机构

Zielbio, Inc.

原研机构

Zielbio, Inc.

在研适应症

胆管上皮癌 [+2]

非在研适应症-

最高研发阶段临床1/2期

首次获批国家/地区-

首次获批日期1800-01-20

ZB131-MMAE ADC

靶点-

作用机制

plectin抑制剂

在研机构

Zielbio, Inc.

原研机构

Zielbio, Inc.

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

ZB131-DXd ADC

靶点-

作用机制

plectin抑制剂

在研机构

Zielbio, Inc.

原研机构

Zielbio, Inc.

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 plectin 相关的临床试验

NCT05074472 / Completed临床1/2期

A Phase 1/2, First-in-Human, Open Label, Dose Escalation Study Of A Cancer-Specific Plectin (CSP)-Targeting Functional Antibody in Solid Tumors That Are Likely to Express CSP

This study is a first-in-human, Phase 1, open label, multicenter, dose escalation study with expansion at the RP2D, to evaluate the safety, tolerability, and preliminary efficacy of ZB131 in patients with solid tumors where prevalence of CSP expression is high. Approximately 12 to 24 patients will be enrolled in the Dose Escalation Stage; the total number of patients will depend on the dose level at which the RP2D is defined. Patients who meet the eligibility criteria during Screening will enter the treatment period. ZB131 will be given via IV every week. Patients will be treated until disease progression or unacceptable toxicities occur.

开始日期2022-01-14

申办/合作机构

Zielbio, Inc.

100 项与 plectin 相关的临床结果

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100 项与 plectin 相关的转化医学

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0 项与 plectin 相关的专利（医药）

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805

项与 plectin 相关的文献（医药）

2024-02-16·Anais brasileiros de dermatologia

Advantages of whole-exome sequencing over immunomapping in 67 Brazilian patients with epidermolysis bullosa.

Article

作者: Samantha Vernaschi Kelmann ; Bruno de Oliveira Stephan ; Silvia Maria de Macedo Barbosa ; Rita Tiziana Verardo Polastrini ; Zilda Najjar Prado de Oliveira ; Maria Cecília Rivitti-Machado ; Gustavo Marquezani Spolador ; Rachel Sayuri Honjo ; Ken Saida ; Naomichi Matsumoto ; Chong Ae Kim

BACKGROUND:

Epidermolysis bullosa (EB) is characterized by skin fragility and blistering. In Brazil, the diagnosis is usually obtained through immunomapping, which involves a skin biopsy. Most recently, whole exome sequencing (WES) has become an important tool for the diagnosis of the subtypes of EB, providing information on prognosis as well as allowing appropriate genetic counseling for the families.

OBJECTIVE:

To compare the results of immunomapping and molecular analysis and to describe the characteristics of a Brazilian cohort of patients with EB.

METHODS:

Patients were submitted to clinical evaluation and WES using peripheral blood samples. WES results were compared to those obtained from immunomapping testing from skin biopsies.

RESULTS:

67 patients from 60 families were classified: 47 patients with recessive dystrophic EB (DEB), 4 with dominant DEB, 15 with EB simplex (EBS), and 1 with junctional EB (JEB). Novel causative variants were: 10/60 (16%) in COL7A1 associated with recessive DEB and 3 other variants in dominant DEB; one homozygous variant in KRT5 and another homozygous variant in PLEC, both associated with EBS. Immunomapping was available for 59 of the 67 patients and the results were concordant with exome results in 37 (62%), discordant in 13 (22%), and inconclusive in 9 patients (15%).

STUDY LIMITATIONS:

Even though EB is a rare disease, for statistical purposes, the number of patients evaluated by this cohort can still be considered limited; other than that, there was a significant difference between the proportion of types of EB (only one case with JEB, against more than 50 with DEB), which unfortunately represents a selection bias. Also, for a small subset of families, segregation (usually through Sanger sequencing) was not an option, usually due to deceased or unknown parent status (mostly the father).

CONCLUSION:

Although immunomapping has been useful in services where molecular studies are not available, this invasive method may provide a misdiagnosis or an inconclusive result in about 1/3 of the patients. This study shows that WES is an effective method for the diagnosis and genetic counseling of EB patients.

2024-02-14·Current medicinal chemistry

Identifying Hub Genes for Glaucoma Based on Bulk RNA Sequencing Data and Multi-machine Learning Models.

Article

作者: Yangyang Xie ; Kai Yu

AIMS:

The aims of this study were to determine hub genes in glaucoma through multiple machine learning algorithms.

BACKGROUND:

Glaucoma has afflicted many patients for many years, with excessive pressure in the eye continuously damaging the nervous system and leading to severe blindness. An effective molecular diagnostic method is currently lacking.

OBJECTIVE:

The present study attempted to reveal the molecular mechanism and gene regulatory network of hub genes in glaucoma, followed by an attempt to reveal the drug-gene-disease network regulated by hub genes.

METHODS:

A microarray sequencing dataset (GSE9944) was obtained through the Gene Expression Omnibus database. The differentially expressed genes in Glaucoma were identified. Based on these genes, we constructed three machine learning models for feature training, Random Forest model (RF), Least absolute shrinkage and selection operator regression model (LASSO), and Support Vector Machines model (SVM). Meanwhile, Weighted Gene Co-Expression Network Analysis (WGCNA) was performed for GSE9944 expression profiles to identify Glaucoma-related genes. The overlapping genes in the four groups were considered as hub genes of Glaucoma. Based on these genes, we also constructed a molecular diagnostic model of Glaucoma. In this study, we also performed molecular docking analysis to explore the gene-drug network targeting hub genes. In addition, we evaluated the immune cell infiltration landscape in Glaucoma samples and normal samples by applying CIBERSORT method.

RESULTS:

8 hub genes were determined: ATP6V0D1, PLEC, SLC25A1, HRSP12, PKN1, RHOD, TMEM158 and GSN. The diagnostic model showed excellent diagnostic performance (area under the curve=1). GSN might positively regulate T cell CD4 naïve as well as negatively regulate T cell regulation (Tregs). In addition, we constructed gene-drug networks in an attempt to explore novel therapeutic agents for Glaucoma.

CONCLUSION:

Our results systematically determined 8 hub genes and established a molecular diagnostic model that allowed the diagnosis of Glaucoma. Our study provided a basis for future systematic studies of Glaucoma pathogenesis.

2024-02-05·Food chemistry

Solubilization of fish myofibrillar proteins in NaCl and KCl solutions: A DIA-based proteomics analysis.

Article

作者: Xidong Jiao ; Xingying Li ; Nana Zhang ; Bowen Yan ; Jianlian Huang ; Jianxin Zhao ; Hao Zhang ; Wei Chen ; Daming Fan

Understanding the basic solubilization of fish myofibrillar proteins (MPs) in common monovalent chloride solutions is crucial for muscle food processing. In this study, the differential proteomic profiles of MPs during extraction and solubilization in NaCl and KCl solutions were investigated by using advanced four-dimensional data-independent acquisition (4D DIA) quantitative proteomics for the first time. Compared to routine biochemical analysis, this could provide insights into the solubilization of muscle proteins. We ensure the consistency of the effective ionic strength of NaCl and KCl buffers by adjusting the conductivity. The results showed that NaCl extractor mainly facilitated the solubilization of cytoskeletal proteins, biochemical enzymes, and stromal proteins compared to KCl, such as tubulin, myosin-9, collagen, plectin, protein phosphatase, and cathepsin D. However, no significant difference was observed in the extraction of major sarcomeric proteins, including myosin, actin, troponin C, myosin-binding protein C, M-Protein, α-actinin-3, and tropomyosin.

项与 plectin 相关的新闻（医药）

2023-07-21

·生物制品圈

超全！国内外circRNA合成技术全面整理

近年来，包括信使RNA（mRNA）、小干扰RNA（siRNA）和微小RNA（miRNA）在内的核糖核酸（RNA）治疗已经迅速发展为现代医学的一个新支柱。其中，基于mRNA制备而成的新冠疫苗更是在抗击引起严重急性呼吸道综合症的新型冠状病毒（SARS-CoV-2）方面发挥了巨大作用，其超快的序列设计速度和易于大规模生产的特性为应对紧急和不断变化的医疗危机提供了新的可能。在如今mRNA药物获得成功的大背景下，将线性mRNA进一步通过首位连接合成环状RNA（circular RNA, circRNA）来提高mRNA的稳定性并延长蛋白质的翻译时间又成为了mRNA治疗领域的新热点。简单来说，环状RNA是一种首尾共价连接的闭合单链RNA，它无需mRNA中常见的5’帽子和3’-poly(A)尾巴就可以保持稳定的状态，这是由于其共价闭合的结构本身就可以阻止核酸酶的降解。生物体内天然形成的环状RNA大多由mRNA前体（pre-mRNA）通过反向剪接（back-splicing）形成，并分布于细胞质中，其半衰期从18.8小时到23.7小时不等，而其同源的线性RNA半衰期仅有4.0~7.4小时。虽然大多数天然的环状RNA是非编码RNA，即不能翻译成蛋白质的RNA，但有研究证明人工合成带有IRES（内部核糖体进入位点）序列的环状RNA是可以在体内和体外进行翻译的。因此，近年来有越来越多的国内外研究人员和生物公司在研究环状RNA在体内外翻译机制，同时研发出多种体内外合成环状RNA的技术，这些技术也极大地促进了环状RNA治疗领域的发展。基于以上背景，本文将从体外合成环状RNA、体内合成环状RNA以及国内外各大环状RNA公司采用的合成方法这三个方面进行阐述，期望提高人们对环状RNA治疗领域的了解。体外合成环状RNA的技术方法1.1 化学合成环状RNA目前环状RNA的化学合成技术主要以磷酰胺（phosphoramidite）化学和固相合成为基础，并以天然的核苷三磷酸酯衍生物为原材料来进行制备的。这些衍生物采用非活性保护基团取代天然核苷三磷酸酯中的反应性氨基和羟基，能够实现3’-5’磷酸二酯连接并去除保护性基团，同时能最大程度避免2’-5’磷酸二酯键的形成及其它副反应的发生。后续经过合成后的处理和纯化，就可以生成高纯度的寡核苷酸。然而，目前的环状RNA化学合成技术只能合成少于70~80个核苷酸（nt）长度的环状RNA（图1）。图1：体外化学合成环状RNA1.2 酶促连接合成环状RNA酶促连接合成通常通过体外转录（IVT）反应实现，该反应需要DNA模板、反应缓冲液和噬菌体RNA聚合酶。噬菌体RNA聚合酶通常来源于T7、SP6或T3噬菌体，其中较常见的是T7 RNA聚合酶。IVT反应允许以较低的成本进行更长的环状RNA合成，因此酶促合成是目前主流的环状RNA合成方法。但需注意的是，野生型噬菌体聚合酶自带的run-off性质可能导致合成不完整的RNA序列，因此有些研究通过突变野生型噬菌体RNA聚合酶来改善体外转录的质量，减少副反应的发生。由于酶促连接是现阶段使用较多的体外合成环状RNA的方法，因此下文将对酶促合成进行重点介绍，而酶促连接又可进一步分为T4连接酶连接和核酶连接两种。1.2.1 T4连接酶合成环状RNA来源于噬菌体T4的多种连接酶都可以催化RNA连接反应，这其中包括T4 DNA连接酶（T4 Dnl）、T4 RNA连接酶1（T4 Rnl 1）和T4 RNA连接酶2（T4 Rnl 2）。当然，这种连接需要线性RNA前体上的受体区域（acceptor substrate）有3’-OH，且供体区域（donor substrate）有5’单磷酸才能进行。1) T4 Dnl连接T4 Dnl可以连接双链DNA或DNA/RNA杂交链（图2A），该方法通常需要利用一个与连接处互补的DNA（cDNA）模板或cDNA“桥”（bridge）来实现。这种方法的优点是连接的准确性较高，但是它要求线性RNA前体在连接处没有明显的RNA二级结构，且在双链区不能有高比例的尿嘧啶（U）。此外，T4 Dnl针对DNA/RNA杂交链的连接效率低于双链DNA（dsDNA）连接，因此实际上只有少数研究会使用该方法进行RNA连接。2) T4 Rnl 1连接T4 Rnl 1是一种比较常见的单链RNA（ssRNA）连接酶，它可催化单链RNA末端的3’-OH对活性的5’端进行亲核攻击，形成共价的3’-5’-磷酸二酯键，进而形成环状RNA（图2B）。有些研究也会在此过程中使用cDNA“桥”来防止线性RNA前体折叠成不必要的二级结构。值得注意的是，T4 Rnl 1对5’末端和3’末端的核苷酸明显偏好性：其对3’末端的核苷酸偏好为A>G≥C>U，而对5’末端核苷酸偏好则为pC>pU>pA>pG。该连接方法的优点是仅可以合成极短的环状RNA（短至6~8 nt），但对于较大的RNA分子的连接效率会显著降低。与T4 Dnl类似，线性RNA前体末端若具有明显的RNA二级结构会大大降低T4 Rnl 1的连接效率。此外，该反应还存在分子间末端连接（低聚物）的严重副反应，该副反应会随着线性RNA前体浓度的增加而增加，并会限制环状RNA的产量。3) T4 Rnl 2连接T4 Rnl 2与T4 Rnl 1相似，它也可催化RNA末端的3’-OH与5’末端形成共价的3’-5’-磷酸二酯键。不过T4 Rnl 2在连接双链RNA（dsRNA）时要比连接单链RNA厉害得多（图2C）。基于这一特点，当线性RNA前体折叠成二级结构，即接头区域为双链结构时，T4 Rnl 2的连接效率要比T4 Rnl 1高得多；而且利用外源RNA“夹板”序列（RNA splint），T4 Rnl 2还能实现对单链RNA末端的连接。不过此方法不能用于连接较短的RNA前体，这是因为当线性RNA前体的长度短于30 nt时，其连接处形成的复合物是不稳定的。与T4 Rnl 1一样，T4 Rnl 2也存在对大片段RNA分子连接效率低和副反应多的问题。综上，T4 Dnl和T4 Rnl 1适用于没有复杂二级结构的RNA环化；而T4 Rnl 2更适用于接头区域为双链的线性RNA前体，因此在实际操作中需要根据线性RNA前体的二级结构来选择不同的T4连接酶。需注意的是，所有这些连接酶合成方法都不能实现大片段RNA分子的环化，也不能完全避免分子间末端连接的副反应。图2：T4连接酶合成环状RNA的策略1.2.2 核酶合成环状RNA1） I型内含子自剪接系统（Group I intron self-splicing system）1982年，科学家在四膜虫（Tetrahymena thermophila）的rRNA转录本中首次发现了I型内含子，它同时也是第一个被发现的核酶——无需任何蛋白质的帮助就可以帮助初级转录本RNA进行自我剪接（self-splicing）。自那以后，在许多生物和病毒基因组的tRNA、mRNA和rRNA中也陆续发现了很多能够自我剪接的I型内含子。尽管这些I型内含子来源于完全不同的初级转录本，但它们的催化中心结构却惊人得相似。根据二级结构可将I型内含子划分为10个结构域，并分别命名为P1~P10，其催化中心位于P4-P6（P4, P5, P6）和P3-P9（P3, P7, P8, P9）结构域的交界处，P1和P10则分别为5’和3’剪接位点（splice site），而其他围绕着保守的催化中心的序列则负责维持核酶的稳定性和正确折叠（图3）。图3：Tetrahymena thermophila I型内含子的二级结构示意图利用I型内含子自剪接的特点进行改造的体外合成环状RNA系统正是目前最为常见的体外合成环状RNA的技术，该技术也被称为PIE法（permuted introns and exons），只需GTP和Mg2+就能实现RNA的连接（图4）。图4：PIE法制备环状RNA的原理用于PIE合成的体外转录模板通常采用来自Anabaena tRNALeu基因或T4噬菌体的胸苷酸合成酶（thymidylate synthase, td）基因上的I型内含子序列，这两种I型内含子都已被证实可以高效促进RNA的环化。以td基因内含子改造的PIE系统为例（图5），它主要包含td内含子的5’端内含子序列（5H）、3’端内含子序列（3H）、相邻外显子序列（E1和E2）、内部引导序列（internal guide sequence, IG）、待环化的RNA（RC）以及为促进折叠和稳定内含子而添加的末端同源臂序列。RNA的环化过程大致如下：（1）一个鸟苷亲核物插入RC-5H交界处（5’ SS）并置换RC的3’末端；（2）该鸟苷继续进一步插入3H-RC交界处(3’ SS)，在与RC 5’末端连接时取代3H的3’末端，从而形成环状RNA。由于该催化反应的关键是E1和E2与内含子序列发生碱基互补配对，因此E1和E2序列也都会被纳入新生的环状RNA中。图5：I型内含子PIE系统的二级结构示意图与化学连接和酶促连接相比，PIE方法可用于较大片段的线性RNA前体环化，而且其反应条件和纯化方法也比较简单。现有的研究已经可以通过设计特定的PIE转录模板对几乎任何序列的线性RNA前体进行高效的环状RNA合成。基于以上优势，PIE法是目前研究最多和使用最广泛的RNA连接方法。然而PIE方法仍存在明显缺陷：1. 由于RNA二级结构的复杂性，不同的RNA序列会导致最终形成的环状RNA结构存在巨大差异；2. 此外，由于外源外显子序列的引入，最终形成的环状RNA序列将与原始的线性RNA前体序列不同，这可能会对环状RNA的功能验证产生负面的影响。2） II型内含子自剪接系统（Group II intron self-splicing system）:II型内含子（Group II introns）是一类发现于细菌和细胞器基因组中的可移动遗传物质，它们被认为是真核生物中剪接体内含子和逆转录转座子的祖先，其包含一个具有催化活性的内含子RNA（“核酶”）和一个内含子编码蛋白（intron-encoded protein，IEP），两者共同介导内含子在基因组内进行增殖。II型内含子RNA通过与剪接体内含子类似的转酯反应催化其自身的剪接，产生拼接的外显子和一个切下来的内含子套索RNA（lariat RNA）。IEP是一种多功能的逆转录酶（reverse transcriptase, RT），它能通过稳定具有催化活性的RNA结构来协助剪接。在剪接后，IEP还会与切除的内含子RNA相连，组成一种可以入侵基因组DNA的核糖核蛋白（Ribonucleoprotein, RNP）（图6A）。II型内含子RNA同样具有保守的二级结构，其长度为400~800 nt，大致可分为六个区域DI-DVI（也可称为D1-D6），它们从结构上来看就像一个“车轮”（图6B）。其中DV是活性位点的核心，包含所谓的催化三碱基（catalytic triad）“AGC”和一个“AY”（Y代表碱基C或T）凸起，这两者都能结合具有重要催化作用的Mg2+离子；而DVI包含一个隆起的腺苷作为分支位点（branching site），其2’-OH基团用于亲核攻击内含子5’剪接位点上的磷酸基团，起始剪接反应并形成套索RNA。DI是最大的结构域，包含上下两半部分，其中的EBS1可以与5’剪接位点交界处的内含子结合位点（IBS1）配对，以确定剪接的确切位置；DII和III是两个较小的结构域，对组装活性内含子结构和激活剪接反应方面起着关键作用，其中DIII还可作为“催化效应器”来加速催化反应；DIV是一个茎环（stem-loop）结构，其loop序列上包含maturase（成熟酶）的ORF，靠近其5’端的亚结构域DIVa含有一个对IEP具有高亲和力结合位点（图6B）。II型内含子RNA还具有保守的5’和3’端序列，分别是GUGYG和AY，其与剪接体内含子的保守序列相似（即GU. . . AG）。图6：II型内含子的工作原理及二级结构示意图II型内含子序列上的一系列保守结构域（包括由希腊字母命名的结构域、外显子结合位点EBS和内含子结合位点IBS）还能通过远距离的三级相互作用形成保守的三级结构，进而将相距甚远的序列凝聚在一起形成新的活性部位，该活性部位会结合剪接位点和分支点（branch-point）的核苷酸残基，然后在Mg2+的帮助下来催化连接反应。科学家们基于II型内含子的自催化特性开发出了另一种体外合成环状RNA的PIE技术——利用反向剪接反应（inverse splicing）将一段RNA末端的5’剪接位点与该RNA的3’剪接位点连接起来形成环状RNA（图7）。图7：II型内含子PIE系统的原理图中科院上海营养与健康研究所的王泽峰研究员课题组及其创立的环码生物医药公司在基于II型内含子环化特性开发的体外环化技术以及环状RNA的体外翻译机制领域就取得了较大突破。他们于2022年发表了一个基于II型内含子环化且适用于大规模生产的体外RNA环化新技术，该技术可以实现高效共转录环化RNA的同时又能避免掺入无关序列，而且该环状RNA可以在细胞和小鼠体内进行高效翻译的同时又不会引起严重的先天性免疫反应。具体来说，他们是对来自破伤风杆菌表层蛋白（surface layer protein of Clostridium tetani, ctSLP）的一个II型内含子上的某个loop区域进行了切割，构建了一种分裂的内含子（split-intron）环化系统，然后将需要环化的序列插入到两段内含子中间，该环化序列两端还分别包含两个6 nt的短序列IBS3和IBS1。在体外转录时，RNA前体会通过II型内含子介导的自我剪接反应产生一个包含目的序列的环状RNA和一个分支状内含子RNA（branched intron RNA），该系统也被他们命名为“CirCode”，可以作为一个通用的平台来生产任何指定序列的环状RNA并用于蛋白质翻译（图8）。图8：环码生物体外环化技术CirCode系统的工作原理示意图3）发夹状核酶（Hairpin ribozyme, HPR）HPR可以单链环状DNA为模板通过滚环（rolling circle）反应和自剪接反应产生环状RNA。带有HPR的线性RNA前体会折叠成两种具有切割活性的构象以暴露出3’端和5’端，进而通过自发连接成环状RNA（图9）。这种方法可以高效生产较短的环状RNA，但它的劣势在于由HPR催化的裂解和连接是一种动态平衡，这会导致形成的环状RNA并不稳定；此外，生成的环状RNA中会包含HPR序列，可能对环状RNA的功能产生不利影响。图9：核酶合成环状RNA的策略综合来看，在以上所有酶促连接合成环状RNA的方法中，PIE法显示出较明显的优势，并且被广泛用于基础研究和工业生产中（表1）。但值得注意的是，不同环化策略合成的环状RNA所触发的人体细胞免疫反应程度存在较大差异：中国科学院分子细胞科学卓越创新中心的陈玲玲团队于2021年报道，由I型内含子自剪接系统合成的环状RNA会分别引入~74 nt（td）或~186 nt（Anabaena）的外源序列，这些外源序列会触发较强的先天性免疫反应；相比之下，由T4 RNA连接酶合成的无外源序列掺入的环状RNA表现出最小的免疫原性。表1体外合成环状RNA的方法对比体内合成环状RNA的技术方法与体外合成环状RNA不同，体内合成环状RNA主要采用在活细胞中过表达促进环化的迷你基因序列的质粒载体来实现，待环化的序列会在转录后通过反向剪接反应自然环化。大多数体内RNA环化的迷你基因中包含至少一个待环化的外显子序列以及含有剪接元件的5’和3’端的内含子顺式元件。通过使用不同组合的内含子顺式元件，该技术几乎可以环化任何长度的序列（100 nt到5 kb），内含子顺式元件大致分为四种：(1)具有互补序列的内含子；(2)含有特定蛋白质结合位点的内含子；(3)具有核酶活性的内含子；(4)来自后生动物tRNA的内含子（图10）。2.1 内含子互补序列（intronic complementary sequences, ICS）合成环状RNA根据现有的全转录组高通量测序结果可知，大多数内源性环状RNA的两侧内含子上富含能够反向互补的序列，这些反向互补的侧翼内含子序列通过互补配对拉近待环化序列的上游受体和下游供体剪接位点在空间上的距离，进而促进反向剪接反应的发生。内含子互补序列（ICS）绝大部分来自生物内源基因上的重复片段或非重复片段，也有少量ICS是通过计算机模拟设计出来的，目前科学家们已经能够利用这种内源性的环状RNA形成机制将指定的RNA序列制备成环状RNA。2.1.1 重复性ICS在人类和灵长类动物中最常见的重复序列是Alu元件，它是约300 nt长的富含腺嘌呤（A）的保守序列，由一类短间隔重复元件（short interspersed repeat elements, SINEs）的逆转录元件进化而来。据估计，Alu元件约占人类基因组的11%，尤其在蛋白质编码基因的内含子中大量存在。除了使用灵长类动物内源基因上的Alu元件，还可以使用非灵长动物中能促进环化的内源基因内含子序列，例如来自Zkscan1、Hipk3和Laccase2等基因的内含子（图10）。2.1.2 非重复性ICS非重复性的内源性ICS包括所有跨越侧翼内含子的反向互补序列，例如在小鼠中能产生大量环状RNA的Y染色体性别决定区基因（sex-determining region-Y, Sry）就是一个含有非重复互补序列内含子的典型案例。通过RNA-seq可知在人体内源性环状RNA两侧的内含子中也存在大量的非重复性ICS序列，它们即使只有30~40 nt长也足以进行环化（图10）。2.2 特定蛋白质结合位点合成环状RNA研究表明多种RNA结合蛋白（RNA binding proteins, RBP）在生物体内有促进反向剪接的功能，因此我们可以将这类蛋白的结合位点整合到过表达环化载体中以介导目的RNA的环化。2.2.1 Musclebind (MBL)在果蝇和人类中，RBP蛋白Muscleblind（MBL）可与基因组上特定的保守位点结合促进这些基因座的RNA反向剪接。2014年就有研究人员将MBL结合位点应用到环状RNA的体内合成技术当中，并成功地在果蝇体内和人类细胞中实现高效的环状RNA表达（图10）。2.2.2 Quaking (QKI)RBP蛋白Quaking是另一个能促进反向剪接的反式作用因子，它首次在小干扰RNA（siRNA）的筛选中被发现，并被证明可以调控环状和线性RNA剪接产物的比例。后续研究发现它的作用机制与MBL蛋白大致相同，将QKI结合位点（ACTAACN1-20TAAC）引入到环化序列两侧内含子上就可以促进RNA的体内环化（图10）。除了上述介绍的RBP，还有NF90/110、RBM20、Fus、DHX9等蛋白可以调控环状RNA的体内合成。然而，目前对于这种将RBP结合位点引入到环化载体上的设计是否会存在不利的影响还不太清楚，后续还需要更深入的研究来了解RBP介导的环化反应机制。图10：体内合成环状RNA的方案2.3 使用tRNA内含子合成环状RNA在2015年一项针对果蝇的RNA-Seq分析结果显示，有一类含量丰富的tRNA内含子环状RNA（tRNA intron circular RNAs, tricRNAs）可以既不依赖剪接复合物（spliceosome）也不依赖自催化剪接反应独立产生。它们主要是由一组高度保守的宿主酶对含有内含子的tRNA前体进行切割后，由宿主连接酶RctB对切除的内含子进行分子内连接产生的。该系统已被证明能够在人类和果蝇细胞系中合成长度在75到800 nt的环状RNA：通过在含有果蝇tRNA基因骨架的内含子切割位点之间插入需要环化的RNA序列，就可以产生想要的环状RNA（图11）。图11：基于tRNA设计的体内合成环状RNA方案2019年有研究人员对该系统进行了优化，他们将一段具有自剪接能力的核酶序列取代了tRNA骨架，进一步提高了环化的效率，这种新的质粒构建被称为“龙卷风（Tornado）”系统，它在高效合成与小分子靶标结合的功能性环状RNA适配体（aptamer）方面具有强大的优势。2.4 使用PIE系统合成环状RNA在前文描述的体外合成环状RNA技术中属PIE法同样可以应用于体内合成环状RNA。假如在质粒载体中插入改造过的I型内含子PIE序列，将其转染到细胞中就可以获得目的序列的环状RNA。与上述体内环化系统不同，含有PIE序列的质粒首先会产生线性转录物，然后通过核酶介导的自剪接反应进行环化。早在90年代就已利用PIE法在大肠杆菌和酵母体内使用改造后的td基因骨架的质粒实现了环状RNA的体内合成。通过替换不同的外显子序列，此方法可以在生物体内（主要是细菌和真菌）稳定地合成各种中短长度的环状RNA（71~1130 nt），这种方式生成的环状RNA类似于从相同PIE序列的IVT反应中获得的剪接产物。但是在2017年的一项研究发现，将含有PIE序列的质粒转染到HeLa细胞中会强烈刺激细胞产生先天性免疫信号，导致转染细胞死亡；然而一个具有相同外显子序列但由ZKSCAN1基因内含子介导体内合成的环状RNA不会导致细胞死亡。造成该现象的原因可能是内含子序列的身份来源影响了环状RNA引起的先天性免疫反应，该发现也提醒我们免疫原性是我们在选择体内还是体外环化系统时必须要考虑的问题，其中体外环化系统可能更适合于没有哺乳动物mRNA剪接和先天性免疫信号系统的非后生动物，关于体内合成环状RNA方法的优劣势对比可参见下表（表2）。表2体内合成环状RNA的方法对比国内外各大环状RNA公司所采用的合成方法因为环状mRNA治疗是近几年才兴起的生物医药领域，所以开发环状RNA治疗的公司相对较少并且都很年轻。在国际上主要以ORNA Therapeutics和Laronde为代表，前者于2022年8月16日刚刚完成2.21亿美元的B轮融资，并且还与默沙东（MSD）公司达成一项总额高达36.5亿美元的合作协议；后者则获得了曾孵化Moderna公司的Flagship的4.4亿美元B轮融资。3.1 Orna Therapeutics该公司于2021年由来自麻省理工学院（MIT）的纳米治疗领域的顶级学者Daniel G. Anderson教授创办，它致力于开发一种完全工程化的环状RNA——oRNA疗法，用以治疗各种疾病，包括癌症、自身免疫性疾病和遗传性疾病。值得一提的是，Anderson实验室正是最早改造鱼腥藻（Anabaena）I型内含子实现体外合成长编码环状RNA的团队，因此Orna公司的环状RNA合成技术也主要采用了I型内含子自剪接系统（图3）。图12：oRNA合成策略Orna公司目前最为领先的项目是原位嵌合抗原受体（CAR）疗法（isCARTM，一种抗CD19的CAR），该疗法结合了oRNA和定制化的脂质纳米颗粒（LNP），可在患者体内制造出改良的免疫细胞用于治疗癌症。为此该公司还开发了一个专有的FoRCE筛选平台用于筛选新的IRES元件，新型IRES能够显著促进oRNA的表达水平（图13）。图13：FoRCE 筛选平台（来源：Orna）Orna在2020年5月后已申请了至少六项与环状mRNA组成和技术相关的专利，所有这些专利申请都披露了环状RNA的结构（包括IRES元件、间隔序列、序列修饰、稳定性）、环状RNA-LNP配方和CAR疗法的传递效率等实验数据。3.2 LARONDELARONDE公司由Flagship Pioneering公司于2021年5月成立，它致力于开发一种名为Endless RNATM（eRNA）的工程化环状RNA，用以表达治疗性蛋白质。LARONDE的知识产权由Flagship Pioneering公司拥有，其申请的专利涵盖了从环状RNA结构、疫苗接种、异源蛋白表达和治疗用途等应用的各个方面，目前已提交了至少12项专利，这其中也包含针对SARS-CoV-2的环状RNA疫苗。尽管LARONDE官网并没有太多它所使用的环状RNA技术的信息，但从其提交的专利来看，该公司主要采用的是T4 Dnl/Rnl连接的方式进行RNA环化。国内环状RNA治疗的生物公司呈现百花齐放百家争鸣的发展趋势，各个环状RNA公司的RNA环化技术各具特色，同时基于环状RNA的递送技术平台、肿瘤免疫、传染病治疗和基因治疗等项目上也在迅速推进。3.3 北京圆因生物（THERORNA）圆因生物于2021年4月由北京大学生命科学学院魏文胜教授创立，魏文胜教授也是基因编辑公司博雅辑因的科学创始人。圆因生物在2022年6月完成近3亿元的A轮融资，专注于利用其专有的环状RNA技术平台来开发下一代疫苗和创新疗法，特别是针对SARS-CoV-2的疫苗。他们在2022年5月发表的Cell文章中报道了编码SARS-CoV-2 spike三聚体RBD抗原的环状RNA疫苗能够在小鼠和猕猴体内引起有效的中和抗体和T细胞反应，且针对SARS-CoV-2野生型及突变株设计的不同环状RNA疫苗均能给提供有力的免疫保护（图14）。他们已于2021年8月提交了相关专利。从专利和文献中可以看出，圆因生物公司主要采用的是与ORNA公司类似的Anabaena I型内含子自剪接系统进行环状RNA的体外合成（图14）。图14：基于I型内含子自剪接的CircRNARBD环化示意图3.4 苏州科锐迈德（Curemed）苏州科锐迈德于2021年8月成立，尽管这是一个相当年轻的公司，但他们已发表了至少四篇基于环状RNA制备、肿瘤治疗和递送的论文，展示出其在环状RNA领域的巨大潜能。科锐迈德目前主要的研究成果包括：1）研发了一种针对新冠病毒的环状mRNA疫苗-cmRNA-1130，该环状mRNA疫苗可在小鼠体内诱导强大的免疫激活以及CD4+ T和CD8+ T细胞；2）在小鼠模型上首次证实了直接肿瘤内注射环状 mRNA 编码的细胞因子混合物，能够调节瘤内系统性抗肿瘤免疫反应，并增强抗 PD-1 单抗的肿瘤抑制效果；3）开发了基于环状mRNA的新型靶蛋白降解平台，利用环状mRNA编码bioPROTAC分子来降解靶蛋白，并将其命名为RiboPROTAC。在环化技术上，科锐迈德还建立了一套基于T4 td基因I型内含子自剪接的剪接位点自动化筛选优化系统，该系统可以找到最优成环位点，然后通过蛋白编码区或IRES连接成环实现无外源序列引入的环状RNA，且成环效率超过90%，该新型环状RNA体外合成技术被命名为“Clean-PIE”（图15）。据悉该成环系统已申请专利，在核酸疫苗、蛋白替代、基因治疗等领域具有良好的应用前景。图15：基于I型内含子自剪接系统开发的Clean-PIE系统3.5 环码生物（Circode Bio）环码生物成立于2018年，由在RNA领域深耕多年的中科院上海营养与健康研究所的王泽峰研究员和杨赟副研究员联合创立。王泽峰团队在2014年发现环状RNA可在人细胞内翻译生成不同功能的蛋白，颠覆了环状RNA是非编码RNA的认知，并开创了环状RNA作为一种新型mRNA疗法的应用。该公司已于2021年完成天使轮和Pre-A轮融资。环码生物拥有自主研发的体外环化专利，该环化技术利用了II型内含子自剪接核酶的活性可在体外环化任意长度的RNA（2~10 kb），该技术具有无外源序列残留、环化产物均一、环化效率高（60%~90%）、反应条件温和等特点，适合于工业化放大（图8）。此外，环码生物也非常注重对序列元件的系统性优化，他们建立了一套基于环状RNA的高通量筛选系统，用于高效筛选翻译起始元件，目前已完成数百万条序列的筛选并获得了大量翻译起始元件。在此基础上，还利用计算生物学的方法建立了针对环状RNA的序列设计优化平台，该平台可以设计优化翻译起始元件及编码区序列从而实现环状RNA的高效翻译。3.6 启环生物苏州启环生物医药成立于2022年3月，其首席科学家是在circRNA领域有着十余年研究积累的中国科学技术大学生命科学与医学部单革教授。启环生物专注环状RNA在生物预防和治疗方向的研发与应用，成立之初就不断探寻新的体外剪接成环方式，结合经典I型和II型内含子结构研究，进而建立了独创的结构组件和环化系统。目前已在IRES、体外环化和circRNA纯化技术方面突破国际专利壁垒，实现体外合成circRNA在生物治疗产业的技术革新，并提交多项国内外专利。启环公司利用自主研发的成环系统结合高效IRES翻译起始元件，已与国内外相关企业合作，在多条基于circRNA表达和调控的生物疗法管线进行布局。3.7 吉赛生物吉赛生物成立于2010年6月，是国内最早（2014年）布局环状RNA领域的公司，拥有深厚的原创技术积淀，已获得环状RNA领域国家发明专利12项。目前拥有全球独有的环化核心专利技术，已完成环状RNA制备整套生产工艺体系开发，建立了四大技术平台：环状RNA序列设计优化平台、环状RNA生产制备平台、环状RNA纯化平台、核心原料酶生产平台，可为全球环状RNA药物研发企业提供CRO服务和原料酶产品。从已申请的专利来看，吉赛生物主要采用T4 Rnl2连接进行环状RNA的体外合成。此外吉赛生物生信部还联合多伦多大学创建了专门的circBank数据库（网址：http://www.circbank.cn/），为环状RNA研究者提供最全面的人类环状RNA注释、circRNA-miRNA调控、翻译潜能预测、疾病突变位点、m6A修饰和环状RNA结构可视化等信息。总结与展望环状RNA因其卓越的稳定性有可能成为一个有效和安全的新一代疫苗接种平台。此前人工合成环状RNA大多是依靠以生物化学为基础的体外策略，但近年来出现了一些基于分子生物学的新方法，使得环状RNA可以直接在活细胞中产生。可以想象在未来将会诞生更多优良和标准化的人工环状RNA制备方法，而这些先进的环状RNA制备方法也必将大幅推进环状RNA生物学功能和分子机制的研究进程。参考资料[1] Chen R, Wang S K, Belk J A, et al. Engineering circular RNA for enhanced protein production[J]. Nature Biotechnology, 2022.[2] Liu C-X, Chen L-L. Circular RNAs: Characterization, cellular roles, and applications[J]. Cell, 2022.[3] Chen X, Lu Y. Circular RNA: Biosynthesis in vitro[J]. Frontiers in Bioengineering and Biotechnology, 2021.[4] Liu X, Zhang Y, Zhou S, et al. Circular RNA: An emerging frontier in RNA therapeutic targets, RNA therapeutics, and mRNA vaccines[J]. Journal of Controlled Release, 2022.[5] Lee C H, Han S R, Lee S-W. Group I Intron-Based Therapeutics Through Trans-Splicing Reaction[J]. Progress in Molecular Biology and Translational Science, 2018.[6] Belfort M, Lambowitz A M. Group II Intron RNPs and Reverse Transcriptases: From Retroelements to Research Tools[J]. Cold Spring Harbor Perspectives in Biology, 2019.[7] Lambowitz A M, Zimmerly S. Group II Introns: Mobile Ribozymes that Invade DNA[J]. Cold Spring Harbor Perspectives in Biology, 2011.[8] Chen C, Wei H, Zhang K, et al. A flexible, efficient, and scalable platform to produce circular RNAs as new therapeutics[J]. bioRxiv, 2022: 2022.05.31.494115.[9] Obi P, Chen Y G. The design and synthesis of circular RNAs[J]. Methods, 2021, 196: 85–103.

信使RNAsiRNA寡核苷酸核酸药物

2023-06-07

·PRNewswire

Cholangiocarcinoma Clinical Trial Pipeline Analysis Demonstrates 65+ Key Companies at the Horizon Expected to Transform the Treatment Paradigm, Assesses DelveInsight

The prevalence of cholangiocarcinoma has been rising over the past few years, which prompts the growing demand for treatment options. The increasing prevalence of cholangiocarcinoma and the growing research and development activities to develop novel therapies to treat cholangiocarcinoma to drive the market. The companies developing the potential therapies in the last stage of development include Eisai, Janssen Research & Development, 3D Medicines, and several others. LAS VEGAS, June 7, 2023 /PRNewswire/ -- ' Cholangiocarcinoma Pipeline Insight – 2023 ' report provides comprehensive global coverage of pipeline cholangiocarcinoma therapies in various stages of clinical development, major pharmaceutical companies working to advance the pipeline space and future growth potential of the cholangiocarcinoma pipeline domain. Key Takeaways from the Cholangiocarcinoma Pipeline Report DelveInsight's cholangiocarcinoma pipeline report depicts a robust space with 65+ active players working to develop 70+ pipeline therapies for cholangiocarcinoma treatment. Key cholangiocarcinoma companies such as Merck KGaA, Eisai Inc., Janssen Research & Development, LLC, 3D Medicines, Basilea Pharmaceutica, Hutchison Medipharma Limited, Jiangsu HengRui Medicine, TransThera Sciences, RedHill Biopharma, Eli Lilly and Company, Elevation oncology, Senhwa Biosciences, InnoCare Pharma, Genoscience Pharma, Intensity therapeutics, Elucida Oncology, GlaxoSmithKline, Verismo Therapeutics, Sirnaomics, Toray Industries, Inc, Kinnate Biopharma, Boehringer Ingelheim, Wellmarker Bio, Arbele Limited, NGM Biopharmaceuticals, Inc., Elicio Therapeutics, Xencor, Inc., Celon Pharma SA, and others are evaluating new cholangiocarcinoma drugs to improve the treatment landscape. Promising cholangiocarcinoma pipeline therapies in various stages of development include Camrelizumab, Niraparib, Irinotecan Liposome, ABC294640, Bintrafusp alfa, TT-00420, Erdafitinib, E7090, 3D185, HMPL-453, Derazantinib, Abemaciclib, Seribantumab, CX-4945, ICP-192, GNS561, INT230-6, SynKIR-110, STP705, LY3410738, TRK-950, KIN-3248, BI 905711, WM-S1-030, ARB202, NGM831, ELI-002 2P, XmAb20717, CPL304110, and others. In May 2023, Richard Kim discussed the investigation of RLY-4008 for the treatment of patients with cholangiocarcinoma harboring an FGFR2 fusion or rearrangement. RLY-4008 is a highly selective, irreversible FGFR2 inhibitor currently under evaluation in the phase 1/2 REFOCUS trial (NCT04526106). Preliminary data reported at the 2022 ESMO Congress showed that patients with FGFR inhibitor–naïve cholangiocarcinoma who had an FGFR2 fusion or rearrangement (n = 17) experienced an overall response rate of 88.2%. In April 2023, Nuvectis Pharma provided highlights from the poster presentation of NXP800 at the American Association for Cancer Research ("AACR") Annual Meeting 2023 in Orlando, FL. The robust preclinical activity demonstrated by NXP8000 in these CCA PDX models was believed to be served as good indicators for potential clinical benefit. CCA is a very difficult-to-treat disease with poor outcomes and today's results provide promise for patients in the future. In April 2023, Verismo Therapeutics received fast-track designation from the US Food and Drug Administration (FDA) for its investigational new drug, SynKIR-110.SynKIR-110 is an investigational drug to treat serious diseases and life-threatening conditions, specifically mesothelin-expressing mesothelioma, ovarian cancer, and cholangiocarcinoma. In January 2023, Taiho Oncology, Inc. announced the publication of results from the pivotal Phase 2 FOENIX*-CCA2 clinical trial of futibatinib in the January 19, 2023 issue of The New England Journal of Medicine (NEJM). In the FOENIX-CCA2 trial, futibatinib showed clinically meaningful benefit in previously treated patients with FGFR2 fusion/rearrangement-positive iCCA, including an objective response rate of 42%, as assessed by independent review, and a median response duration of 9.7 months. Treatment with futibatinib resulted in durable responses and survival that surpassed historical data with chemotherapy in patients with previously treated iCCA. In October 2022, Invitae announced a partnership with AstraZeneca to use Invitae's Ciitizen natural history data in a retrospective and prospective study of patients diagnosed with cholangiocarcinoma, a rare bile duct cancer. This partnership will enable sharing of high-quality, patient-consented data from the patient community of the Cholangiocarcinoma Foundation (CCF), a leading patient advocacy group whose mission is to find a cure and improve the quality of life for those with cholangiocarcinoma. In November 2022, The FDA granted orphan drug designation to ZB131 for treatment of cholangiocarcinoma, according to the agent's manufacturer. ZB131 (ZielBio) is a monoclonal antibody with a high affinity and specificity for cancer-specific plectin. Request a sample and discover the recent advances in cholangiocarcinoma drug treatment @ Cholangiocarcinoma Pipeline Report The cholangiocarcinoma pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage cholangiocarcinoma drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the cholangiocarcinoma clinical trial landscape. Cholangiocarcinoma Overview Cholangiocarcinoma is an epithelial cell cancer that arises from several places within the biliary network and exhibits cholangiocyte differentiation markers. The most recent anatomical classifications include intrahepatic, perihilar, and distal cholangiocarcinoma. Many occurrences of cholangiocarcinoma occur without a specific risk factor, but a variety of risk factors have been found, including primary hepatobiliary illness, genetic diseases, toxic exposures, and infections. Like many other cancers, cholangiocarcinoma develops from precursor lesions such as the more common biliary intraepithelial neoplasia and the less common intraductal papillary mucinous neoplasm. Mutations in various oncogenes and tumor suppressor genes cause the normal epithelium to become one of these premalignant lesions. Cholangiocarcinomas have mutations in genes such as RAS, BRAF, p52, SMAD4, and others, but the exact molecular mechanism has not been discovered. Basic laboratory tests for the liver should include aminotransferases, alkaline phosphatase, and total/indirect/direct bilirubin. Cholangiocarcinoma can be treated medically or surgically, although surgery is the only curative option. Find out more about drugs for cholangiocarcinoma @ New Cholangiocarcinoma Drugs A snapshot of the Cholangiocarcinoma Pipeline Drugs mentioned in the report: Learn more about the emerging cholangiocarcinoma pipeline therapies @ Cholangiocarcinoma Clinical Trials Cholangiocarcinoma Therapeutics Assessment The cholangiocarcinoma pipeline report proffers an integral view of cholangiocarcinoma emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Cholangiocarcinoma Pipeline Report Coverage: Global Cholangiocarcinoma Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Cholangiocarcinoma Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Cholangiocarcinoma Therapeutics Assessment By Route of Administration: Oral, Parenteral, Intravitreal, Subretinal, Topical Cholangiocarcinoma Therapeutics Assessment By Molecule Type: Monoclonal Antibody, Peptides, Polymer, Small molecule, Gene therapy Cholangiocarcinoma Therapeutics Assessment By Mechanism of Action: Type 1 fibroblast growth factor receptor antagonists, Type 3 fibroblast growth factor receptor antagonists, Type 4 fibroblast growth factor receptor antagonists, Type-2 fibroblast growth factor receptor antagonists, Programmed cell death-1 receptor antagonists, Bcr-abl tyrosine kinase inhibitors, EphA2 receptor antagonists, Platelet-derived growth factor beta receptor antagonists, Proto oncogene protein c-kit inhibitors, Src-Family kinase inhibitors, Antibody-dependent cell cytotoxicity, Programmed cell death-1 receptor antagonists, T lymphocyte stimulants, Poly(ADP-ribose) polymerase 1 inhibitors, Poly(ADP-ribose) polymerase 2 inhibitors Key Cholangiocarcinoma Companies: Merck KGaA, Eisai Inc., Janssen Research & Development, LLC, 3D Medicines, Basilea Pharmaceutica, Hutchison Medipharma Limited, Jiangsu HengRui Medicine, TransThera Sciences, RedHill Biopharma, Eli Lilly and Company, Elevation oncology, Senhwa Biosciences, InnoCare Pharma, Genoscience Pharma, Intensity therapeutics, Elucida Oncology, GlaxoSmithKline, Verismo Therapeutics, Sirnaomics, Toray Industries, Inc, Kinnate Biopharma, Boehringer Ingelheim, Wellmarker Bio, Arbele Limited, NGM Biopharmaceuticals, Inc., Elicio Therapeutics, Xencor, Inc., Celon Pharma SA, and others. Key Cholangiocarcinoma Pipeline Therapies: Camrelizumab, Niraparib, Irinotecan Liposome, ABC294640, Bintrafusp alfa, TT-00420, Erdafitinib, E7090, 3D185, HMPL-453, Derazantinib, Abemaciclib, Seribantumab, CX-4945, ICP-192, GNS561, INT230-6, SynKIR-110, STP705, LY3410738, TRK-950, KIN-3248, BI 905711, WM-S1-030, ARB202, NGM831, ELI-002 2P, XmAb20717, CPL304110, and others. Dive deep into rich insights for new drugs for cholangiocarcinoma treatment; visit @ Cholangiocarcinoma Medications Table of Contents For further information on the cholangiocarcinoma pipeline therapeutics, reach out @ Cholangiocarcinoma Drug Treatment Related Reports Cholangiocarcinoma Market Cholangiocarcinoma 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 cholangiocarcinoma companies, including AstraZeneca, Decalth Systems, Basilea Pharmaceutica, Taiho Oncology, Eisai Pharmaceuticals, TransThera Sciences, Incyte Corporation, Roche, among others. Cholangiocarcinoma Epidemiology Forecast Cholangiocarcinoma Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, and cholangiocarcinoma epidemiology trends. Intrahepatic Cholangiocarcinoma Pipeline Intrahepatic Cholangiocarcinoma Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key intrahepatic cholangiocarcinoma companies, including Basilea Pharmaceutica, AstraZeneca, Delcath Systems Inc., Jiangsu HengRui Medicine Co., Ltd., Syndax Pharmaceuticals, Hutchison Medipharma Limited, Medivir, Newish Technology (Beijing) Co., Ltd., Relay Therapeutics, Inc., among others. Intrahepatic Cholangiocarcinoma Market Intrahepatic Cholangiocarcinoma 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 intrahepatic cholangiocarcinoma companies, including Kinnate Biopharma, Taiho Oncology, Inc., Sirtex Medical, Virogin Biotech Ltd, TriSalus Life Sciences, among others. Bile Duct Cancer Pipeline Bile Duct Cancer Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key bile duct cancer companies, including Merck, BMS, Elicio Therapeutics, among others. Biliary Tract Cancers Pipeline Biliary Tract Cancers Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key biliary tract cancers companies, including companies involved such as Merck, RemeGen, EMD Serono, SMT bio Co., Ltd., among others. Related Healthcare Services Healthcare 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 Contact Us Shruti Thakur [email protected] +1(919)321-6187 Logo: SOURCE DelveInsight Business Research, LLP

临床结果快速通道孤儿药临床2期临床1期

2023-06-02

·PRNewswire

ZielBio to Present Interim Findings from its Phase 1/2, First-in-Human Trial of ZB131 at 2023 ASCO Annual Meeting

ZB131 is a first-in-class humanized monoclonal antibody targeting cancer-specific plectin (CSP), which is expressed on the surface of cancer cells in solid tumors Interim data demonstrates safety and tolerability of ZB131 while providing evidence of clinical activity in a proportion of patients with difficult-to-treat tumors CHARLOTTESVILLE, Va., June 2, 2023 /PRNewswire/ -- ZielBio, Inc., a clinical stage biotechnology company discovering new treatments for cancer and other serious diseases, will present the first set of clinical data from its lead asset, ZB131, directed against cancer-specific plectin (CSP), during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. In an interim analysis (n=32) of the Phase 1/2 trial, ZB131 demonstrated a favorable safety and tolerability profile, evidence of clinical activity and dose-proportional pharmacokinetics. Dr. David Sommerhalder, principal investigator at NEXT Oncology in San Antonio, Texas, will present the data in a poster session (board 281) on Saturday, June 3 from 9:00 am to 12:30 pm in poster Hall A at Chicago's McCormick Place. The ZB131 clinical trial (trial identifier NCT05074472) is a Phase 1/2, first-in-human, open-label, dose escalation study of ZB131 in tumors likely to express CSP. The primary objective of the dose escalation phase was to evaluate the safety and tolerability of ZB131 as a monotherapy. Having established safe dosing levels, the study began enrolling expansion cohorts treating patients with either ZB131 at 30 mg/kg as a monotherapy or ZB131 at 15 mg/kg in combination with gemcitabine. "The initial safety, pharmacokinetics and clinical activity from the Phase 1/2 trial, combined with preclinical evidence that ZB131 binds selectively to CSP, rapidly internalizes, and can be conjugated to cytotoxic payloads, validates our efforts to further develop ZB131, including as an antibody-drug conjugate (ADC)," said Alan Bash, CEO of ZielBio. "CSP is a highly promising target given its cell surface expression in malignant tissue and lack of presence in healthy tissue across multiple solid tumors, and ZielBio is leading the field of research into this target." About ZielBio ZielBio is a clinical stage biotechnology company that identifies novel disease targets and develops therapeutic interventions to improve patient outcomes. Its proprietary drug discovery platform ZielFind combines the power of functional, high throughput screening with large content data analytics to identify high value targets. ZielBio has a promising pipeline of therapies and targets, including novel lead asset ZB131 (proposed international nonproprietary name Ibentatug), a proprietary humanized monoclonal antibody against cancer-specific plectin. The company's clinical trial of ZB131 is open and enrolling with additional study details available at clinicaltrials.gov (NCT05074472). SOURCE ZielBio, Inc.

ASCO会议临床1期临床结果