更新于：2024-05-01

NRG1

神经调节蛋白-1

更新于：2024-05-01

基本信息

别名

Acetylcholine receptor-inducing activity、ARIA、Breast cancer cell differentiation factor p45

+ [17]

简介

Direct ligand for ERBB3 and ERBB4 tyrosine kinase receptors. Concomitantly recruits ERBB1 and ERBB2 coreceptors, resulting in ligand-stimulated tyrosine phosphorylation and activation of the ERBB receptors. The multiple isoforms perform diverse functions such as inducing growth and differentiation of epithelial, glial, neuronal, and skeletal muscle cells; inducing expression of acetylcholine receptor in synaptic vesicles during the formation of the neuromuscular junction; stimulating lobuloalveolar budding and milk production in the mammary gland and inducing differentiation of mammary tumor cells; stimulating Schwann cell proliferation; implication in the development of the myocardium such as trabeculation of the developing heart. Isoform 10 may play a role in motor and sensory neuron development. Binds to ERBB4 (PubMed:10867024, PubMed:7902537). Binds to ERBB3 (PubMed:20682778). Acts as a ligand for integrins and binds (via EGF domain) to integrins ITGAV:ITGB3 or ITGA6:ITGB4. Its binding to integrins and subsequent ternary complex formation with integrins and ERRB3 are essential for NRG1-ERBB signaling. Induces the phosphorylation and activation of MAPK3/ERK1, MAPK1/ERK2 and AKT1 (PubMed:20682778). Ligand-dependent ERBB4 endocytosis is essential for the NRG1-mediated activation of these kinases in neurons (By similarity).

关联

重组人纽兰格林（上海泽生）

靶点

NRG1

作用机制

NRG1调节剂

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3期

首次获批国家/地区-

首次获批日期1800-01-20

Recombinant Human Neuromodulin 1-Anti-HER3 Antibody Fusion Protein(Shenzhen Salubris Pharmaceuticals Co., Ltd.)

重组人神经调节蛋白1-抗HER3抗体融合蛋白 (深圳信立泰)

靶点

HER3 x NRG1

作用机制

HER3拮抗剂 [+1]

在研机构

深圳信立泰药业股份有限公司 [+1]

原研机构

深圳信立泰药业股份有限公司

在研适应症

射血分数保留型心力衰竭 [+4]

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

IN-04

靶点

EGF x NRG1

作用机制

EGF抑制剂 [+1]

在研机构

In3Bio Ltd.

原研机构

In3Bio Ltd.

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 NRG1 相关的临床试验

NCT06369298 / Recruiting临床2期

A Phase 2 Randomized, Double-blind, Placebo-controlled Study to Assess the Safety and Efficacy of JK07 in Adults With Chronic Heart Failure (RENEU-HF)

This is a Phase 2, randomized, double-blind, placebo-controlled, multiple dose study to assess the safety, tolerability, and efficacy of JK07 in participants aged 18-85 with heart failure.
There will be 2 cohorts in this study:
Cohort 1: Heart failure (HF) participants with left ventricular ejection fraction (LVEF) of ≤ 40%.
Cohort 2: Heart failure (HF) participants with left ventricular ejection fraction (LVEF) > 40% and ≤ 65%.
Participants in both cohorts will be randomized into either low dose JK07, high dose JK07 or placebo. Participants will have a 2:1 chance of receiving JK07 versus placebo.

开始日期2024-03-28

申办/合作机构

Salubris Biotherapeutics, Inc.初创企业

NCT05949801 / Recruiting临床3期

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Clinical Trial Based on Standard Treatment to Evaluate the Effect of Injectable Neucardin on Cardiac Function and Reverse Ventricular Remodeling in Patients With Chronic Systolic Heart Failure

A multicenter, randomized, double-blind, placebo-controlled phase III clinical trial to evaluate the effect of recombinant human Neuregulin-1 for injection on cardiac function and reverse ventricular remodeling in male patients with NT-proBNP ≤ 1700 pg/ml and female patients with NT-proBNP ≤ 4000 pg/ml and New York Heart Association class II-III chronic systolic heart failure, and to confirm its efficacy and safety.

开始日期2023-04-13

申办/合作机构

上海泽生科技开发股份有限公司

CTR20192276 / Recruiting临床2期

随机、双盲、安慰剂平行对照评价注射用重组人纽兰格林对射血分数保留心力衰竭(HFpEF) 患者安全性和有效性临床试验

随机、双盲、安慰剂平行对照评估注射用重组人纽兰格林对射血分数保留心力衰竭患者(LVEF≥50%)的疗效，并进行安全性评价。

开始日期2022-11-03

申办/合作机构

上海泽生科技开发股份有限公司

100 项与 NRG1 相关的临床结果

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100 项与 NRG1 相关的转化医学

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0 项与 NRG1 相关的专利（医药）

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2,587

项与 NRG1 相关的文献（医药）

2024-02-23·Cell death & disease

nNOS in Erbb4-positive neurons regulates GABAergic transmission in mouse hippocampus.

Article

作者: Chaofan Wan ; Yucen Xia ; Jinglan Yan ; Weipeng Lin ; Lin Yao ; Meng Zhang ; Inna Gaisler-Salomon ; Lin Mei ; Dong-Min Yin ; Yongjun Chen

Neuronal nitric oxide synthase (nNOS, gene name Nos1) orchestrates the synthesis of nitric oxide (NO) within neurons, pivotal for diverse neural processes encompassing synaptic transmission, plasticity, neuronal excitability, learning, memory, and neurogenesis. Despite its significance, the precise regulation of nNOS activity across distinct neuronal types remains incompletely understood. Erb-b2 receptor tyrosine kinase 4 (ErbB4), selectively expressed in GABAergic interneurons and activated by its ligand neuregulin 1 (NRG1), modulates GABA release in the brain. Our investigation reveals the presence of nNOS in a subset of GABAergic interneurons expressing ErbB4. Notably, NRG1 activates nNOS via ErbB4 and its downstream phosphatidylinositol 3-kinase (PI3K), critical for NRG1-induced GABA release. Genetic removal of nNos from Erbb4-positive neurons impairs GABAergic transmission, partially rescued by the NO donor sodium nitroprusside (SNP). Intriguingly, the genetic deletion of nNos from Erbb4-positive neurons induces schizophrenia-relevant behavioral deficits, including hyperactivity, impaired sensorimotor gating, and deficient working memory and social interaction. These deficits are ameliorated by the atypical antipsychotic clozapine. This study underscores the role and regulation of nNOS within a specific subset of GABAergic interneurons, offering insights into the pathophysiological mechanisms of schizophrenia, given the association of Nrg1, Erbb4, Pi3k, and Nos1 genes with this mental disorder.

2024-02-22·Cell communication and signaling : CCS

Impairments of GABAergic transmission in hippocampus mediate increased susceptibility of epilepsy in the early stage of Alzheimer's disease.

Article

作者: Rui Mao ; Mengsha Hu ; Xuan Liu ; Lei Ye ; Bingsong Xu ; Min Sun ; Siyi Xu ; Wenxuan Shao ; Yi Tan ; Yun Xu ; Feng Bai ; Shu Shu

BACKGROUND:

Patients with Alzheimer's disease (AD) are often co-morbid with unprovoked seizures, making clinical diagnosis and management difficult. Although it has an important role in both AD and epilepsy, abnormal γ-aminobutyric acid (GABA)ergic transmission is recognized only as a compensative change for glutamatergic damage. Neuregulin 1 (NRG1)-ErbB4 signaling can promote GABA release and suppress epileptogenesis, but its effects on cognition in AD are still controversial.

METHODS:

Four-month-old APPswe/PS1dE9 mice (APP mice) were used as animal models in the early stage of AD in this study. Acute/chronic chemical-kindling epilepsy models were established with pentylenetetrazol. Electroencephalogram and Racine scores were performed to assess seizures. Behavioral tests were used to assess cognition and emotion. Electrophysiology, western blot and immunofluorescence were performed to detect the alterations in synapses, GABAergic system components and NRG1-ErbB4 signaling. Furthermore, NRG1 was administrated intracerebroventricularly into APP mice and then its antiepileptic and cognitive effects were evaluated.

RESULTS:

APP mice had increased susceptibility to epilepsy and resulting hippocampal synaptic damage and cognitive impairment. Electrophysiological analysis revealed decreased GABAergic transmission in the hippocampus. This abnormal GABAergic transmission involved a reduction in the number of parvalbumin interneurons (PV⁺ Ins) and decreased levels of GABA synthesis and transport. We also found impaired NRG1-ErbB4 signaling which mediated by PV⁺ Ins loss. And NRG1 administration could effectively reduce seizures and improve cognition in four-month-old APP mice.

CONCLUSION:

Our results indicated that abnormal GABAergic transmission mediated hippocampal hyperexcitability, further excitation/inhibition imbalance, and promoted epileptogenesis in the early stage of AD. Appropriate NRG1 administration could down-regulate seizure susceptibility and rescue cognitive function. Our study provided a potential direction for intervening in the co-morbidity of AD and epilepsy.

2024-02-20·mSphere

The role of the C. albicans transcriptional repressor NRG1 during filamentation and disseminated candidiasis is strain dependent.

Article

作者: Rohan S Wakade ; Melanie Wellington ; Damian J Krysan

Candida albicans is one of the most common causes of superficial and invasive fungal diseases in humans. Its ability to cause disease is closely linked to its ability to undergo a morphological transition from budding yeast to filamentous forms (hyphae and pseudohyphae). The extent to which C. albicans strains isolated from patients undergo filamentation varies significantly. In addition, the filamentation phenotypes of mutants involving transcription factors that positively regulate hyphal morphogenesis can also vary from strain to strain. Here, we characterized the virulence, in vitro and in vivo filamentation, and in vitro and in vivo hypha-associated gene expression profiles for four poorly filamenting C. albicans isolates and their corresponding deletion mutants of the repressor of filamentation NRG1. The two most virulent strains, 57055 and 78048, show robust in vivo filamentation but are predominately yeast phase under in vitro hypha induction; the two low-virulence strains (94015 and 78042) do not undergo filamentation well under either condition. In vitro, deletion of NRG1 increases hyphae formation in the SC5314 derivative SN250, but only pseudohyphae are formed in the clinical isolates. Deletion of NRG1 modestly increased the virulence of 78042, which was accompanied by increased expression of hypha-associated genes without an increase in filamentation. Strikingly, deletion of NRG1 in 78048 reduced filamentation in vivo, expression of candidalysin (ECE1), and virulence without dramatically altering establishment of infection. Thus, the function of the conserved repressor NRG1 in C. albicans shows strain-based heterogeneity during infection.IMPORTANCEClinical isolates of the human fungal pathogen Candida albicans show significant variation in their ability to undergo in vitro filamentation and in the function of well-characterized transcriptional regulators of filamentation. Here, we show that Nrg1, a key repressor of filamentation and filament specific gene expression in standard reference strains, has strain-dependent functions, particularly during infection. Most strikingly, loss of NRG1 function can reduce filamentation, hypha-specific gene expression such as the toxin candidalysin, and virulence in some strains. Our data emphasize that the functions of seemingly fundamental and well-conserved transcriptional regulators such as Nrg1 are contextual with respect to both environment and genetic backgrounds.

项与 NRG1 相关的新闻（医药）

2024-03-29

·药渡Daily

短短几年，信立泰的创新管线进展令人惊叹

近日，信立泰发布最新年报，2023年，其总营收33.65亿元，同比下降3.35%；净利润5.8亿元，下降8.95%。虽然在财务指标上，信立泰仍在艰难前行，但相较于三年以前，前路已不再迷茫和焦虑，而是一片坦途。在大手笔砸钱研发之后，信立泰的研发管线进展神速，短短两三年间便已取得巨大进展，眼见着第一梯队的创新产品就要“摘果”了。意料之外的进展信立泰的创新管线与其他Biotech有很大的不同，因为其始终瞄准心脑血管疾病领域需求，在抗血小板、抗凝领域、高血压及心衰领域、慢性肾脏病领域大力布局，持续发力，已形成了短期、中期、长期梯队。在熟悉的领域里努力，确实能少走很多弯路。2023年，信立泰的重点项目取得了诸多阶段性成果：SAL0107、SAL067（苯甲酸福格列汀）、S086（高血压适应症）、SAL0108均已申报上市申请，正在审评中；SAL056（长效特立帕肽）完成III期临床试验并已锁库；S086（慢性心衰适应症）临床III期患者入组已开始；SAL003（重组全人源抗PCSK9单抗）完成III期临床试验的首例患者入组；S086/苯磺酸氨氯地平复方制剂（SAL0130）正在开展联合给药的III期临床等等。信立泰研发管线来源：年报恩那度司他成为信立泰转型以来首款落地的创新药。恩那度司他（Enarodustat）是一种可口服的强效可逆性低氧诱导因子脯氨酰羟化酶抑制剂（HIF-PHI），为治疗肾性贫血的新机制创新药物，既可促进内源性促红细胞生成素的生成，也可改善铁的利用，且具有良好的安全性和有效性，可显著提高患者依从性。信立泰于2019年12月以8750万美元从日本JAPAN TOBACCO INC引进恩那度司他，并于2023年6月上市。恩那度司他是国内第二款HIF-PHI药物，第一款HIF-PHI药物是由珐博进中国和阿斯利康中国在国内合作开发的罗沙司他，于2018年12月获批国内上市。根据药渡数据，罗沙司他销售额从2019年的995万元增加到2023年前三季度的的14.5亿元，是名副其实的大单品。恩那度司他和罗沙司他在疗效性和安全性上相比处于同一水平，有望抢夺罗沙司他市场份额。而且从后续竞争格局看，短期内格局相对温和，只有康哲药业的德度司他最快处于III期临床。国内HIF-PHI靶点肾性贫血治疗药物临床进展来源：德邦证券研报在自研方面，信立泰的几款在研也颇具竞争力。S086（沙库巴曲阿利沙坦钙）是血管紧张素II受体-脑啡肽酶双重抑制剂（ARNi），由信立泰自主研发，是全球第二个进入临床的ARNi类小分子化学药物。全球首款ARNi药物是诺华研制的沙库巴曲缬沙坦钠（商品名：Entresto），2023年，Entresto的全球销售额达到60.35亿美元，成为诺华最畅销的产品。根据药渡数据，2023年前三季度，Entresto在中国的销售额达到30.78亿元。目前，S086的慢性心衰适应症正在III期临床试验的患者入组阶段，轻中度原发性高血压适应症上市申请已于2023年7月获受理，有望于今年面世，有望成为10亿元级别的“爆款”，前景十分值得期待。S086作用机制来源：德邦证券研报此外，信立泰在高血压治疗药物方面，还布局了SAL0107和SAL0108。SAL0107（阿利沙坦酯氨氯地平片）是首个国产ARB/CCB类2类复方制剂，SAL0108(阿利沙坦酯吲达帕胺片)是ARB/NCC类2类复方制剂，未来或将在某些高血压应用场景带来价值，目前两者都已提交是上市申请。心衰领域，JK07是信立泰自主研发、具有全球知识产权的NRG-1融合抗体药物，是心衰领域首个进入临床开发阶段的选择性ErbB4激动剂。全新机制尚无同类产品上市，JK07研发处于同系列药品较快阶段，目前在美国、中国同时开展了I期临床试验。抗凝降脂领域，信立泰自主研发的重组全人源抗PCSK9单抗（SAL003）拟用于高胆固醇血症和混合型高脂血症的治疗，目前处于临床II期阶段；SAL0104（FXIa抑制剂）拟开发适应症为预防、治疗血栓性疾病，目前处于临床I期阶段。另外，SAL056是一款在研的长效特立帕肽，已处于III期，即将申报上市。特立帕肽作为国内唯一骨形成促进剂，疗效和安全性良好。国内特立帕肽生产厂商中，信立泰同时布局了水针、粉针和长效剂型，其水针为国内首仿，粉针剂型为国内二仿，长效剂型在研厂商中仅有信立泰一家公司，产品梯队布局合理。从上述管线中，我们可以看到，诸多较为重磅的在研有望于今年登场，而后续梯队中，也有许多竞争格局较为良好的品种。要知道，在三年以前，信立泰研发管线中的项目还寥寥无几，青黄不接，管线进程的爆发，得益于大手笔地砸钱。转型过渡期已近尾声2023年，信立泰的研发投入达到了10.47亿元，再度增长14.17%，占到总营收比重的31.13%。这么大比重的研发投入，从某种程度来讲，实在是无奈之举。信立泰是仿制药时代躺赢的典型代表，也是集采时代严重受伤的典型代表。在当家产品集采丢标以后，信立泰焦虑感爆表，通过多种手段极力消除集采丢标带来的影响。2020年10月起，信立泰先后卖掉了盐酸达泊西汀、盐酸厄洛替尼、利伐沙班和甲磺酸伊马替尼等仿制药，卖掉M.A.MED ALLIANCE SA约5.69万股股权。同时，信立泰还通过引进战略投资者、非公共发行股票、抛售股权等手段，募集了大量资金。凯雷投资集团（The Carlyle Group Inc.）便是在此时大举进入信立泰。2020年9月，信立泰的控股股东将合计持有的5230万股（占总股本的5%）的信立泰股权，以总价为17.75亿元，通过协议转让给中信里昂，中信里昂背后是凯雷亚洲第五期基金；2021年6月，信立泰发布非公开发行股票上市公告，通过发行数量6880万股的股票，共募集了19.52亿元，包括南方基金、睿远基金、招商证券等18家机构和个人参与了认购。短短时间内，便募集了近40亿元的资金。根据年报，截至2023年年底，信立泰尚有货币现金13.22亿元，金融资产10.6亿元。“烧钱”的速度有点夸张，不过好在阿利沙坦酯已足够强大，已成为信立泰的支柱产品。截至2023年底信立泰的货币现金情况来源：年报信立坦（阿利沙坦酯）是唯一由国内自主研发、拥有自主知识产权（1.1类新药）的血管紧张素II受体拮抗剂类（ARB）降压药物，2013年获批上市，口碑得到市场验证，制剂专利保护期到2028年。阿利沙坦酯生物利用度较高，经济效应优势显著。在同类ARB药物中，对比发现阿利沙坦酯半衰期大概在10h左右，处于同类药品中位，生物利用度达到60%，处于同类药品高位。从市场空间来看，在ARB类整体药物走势疲软的趋势下，阿利沙坦酯销售额和占比持续走高，销售额从2016年的222万元增长到2022年的7.85亿元，市占率也从2016年的不足0.1%提高到2022年的15.2%。根据药渡数据，2023年前三季度，阿利沙坦酯在国内的销售额为6.23亿元。阿利沙坦酯的销售趋势来源：药渡数据集采方面，整体上信立泰存量品种已经基本完成集采。2020年“光脚产品”地氯雷他定、匹伐他汀替格瑞洛等中标第三批集采，2021年替格瑞洛中标第四批集采，2022年头孢吡肟中标第七批集采，集采对于其整体业绩影响趋于缓和，后续仿制药业务有望稳健增长。结语在过去的一段时间里，信立泰总是被当成受集采重挫的典型而反复提及，以至于在人们的印象中，信立泰似乎立马就要撑不住的样子。但这三年来，信立泰能够以最快的速度华丽转身，其前瞻性和果断的态度确实非一般药企能比，从作为集采重创药企的典型，到如今即将收获诸多创新产品，一路走来，不仅勇气可嘉，而且手段果敢老辣，非常值得研究学习。后续发展如何，药渡还将持续关注。参考资料信立泰官网、年报、公告等德邦证券研报《信立泰的“药企进化论”：红利吃尽，集采失利倒逼转型》，钛媒体，2023-06-07

临床3期财报上市批准

2024-03-14

·CPHI制药在线

吉利德斥资15亿美元，押注三抗！Merus 公司究竟有何优势？

关注并星标CPHI制药在线近日，吉利德科学公司（Gilead Sciences）和Merus宣布达成一项研究合作和许可协议，将共同开发靶向新型肿瘤相关抗原（TAA）的三特异性抗体。两家公司将利用Merus专有的Triclonics平台以及吉利德在肿瘤学的专业经验，来共同研究和开发多个独立的临床前研究项目。根据协议条款，Merus将领导两个项目的早期研究活动，并可选择开展第三个项目。在完成选定的研究活动后，吉利德将有权利获得合作开发项目的许可权。如果吉利德自合作项目中行使其选择权，吉利德将负责此类项目的额外研究、开发和商业化活动。Merus将收到5600万美元预付款，以及吉利德对Merus的2500万美元投资。在所有潜在项目中，Merus还有资格获得高达15亿美元的款项，包括潜在的开发和商业化里程碑付款等。三特异性抗体:"小荷才露尖尖角" 随着单抗药物不断拓展的疾病领域，肿瘤复杂的生物学特性、血脑屏障等等因素都限制了抗体疗法的效用。因此，研究人员对抗体疗法进行不断的研究和开发，以克服这些障碍，更大程度的释放抗体药物的潜力。三特异性抗体（三抗）就是这些研究中有潜力的一种。目前，三特异性抗体主要用于肿瘤治疗，三个特异性靶点的抗体结构域中，至少有一个靶向结合T细胞或NK细胞，至少有一个靶向结合肿瘤相关抗原（TAA），它既可以作为免疫细胞衔接器，桥接免疫细胞与肿瘤细胞，也可以只靶向免疫效应细胞或肿瘤细胞来发挥其肿瘤杀伤特性。三特异性抗体有利于将药物重定向至肿瘤局部，增加结合特异性，提升药物靶向肿瘤细胞的准确性及有效性，降低脱靶毒性。三特异性抗体由于具有三个抗原结合位点，其靶向策略非常灵活，具有免疫细胞桥接、免疫细胞激活、双信号通路阻断这三种机制。由于三抗显示出对多种疾病的潜力和更高的特异性，吸引了多家国际制药巨头的青睐，投身于该领域的研发。此外，MNC通过与三抗技术公司达成合作伙伴关系，收购管线等方式布局该领域，获取三抗技术，也进一步吸引了新的投资者。目前，全球三特异性抗体市场尚处于起步阶段，尚未得到产品批准。不过，预计三特异性抗体在预测期内将有较高的增长率。在众多三特异性抗体药物研发管线中，Sanofi、Harpoon Therapeutics、Numab Therapeutics三家公司处于研发前列，最快的药物已进入临床二期阶段。目前，国内三特异性抗体药物研发仍处于初期阶段，布局企业较少，入局者包括基石药业、博锐生物、嘉和生物、泽璟制药、先声药业、启愈生物、惠和生物、恩沐生物等。 Merus独具特色的抗体平台和管线 Merus 是一家创立于2003年，总部位于荷兰临床阶段的免疫肿瘤公司，专注于开发创新的全长多克隆抗体，基于Multiclonics技术平台（包括Biclonics和Triclonics平台），目前已经有7条管线处于临床阶段。 2021年1月19日，Merus与Lilly旗下的Loxo oncology达成合作协议，Merus利用其双特异抗体平台 Biclonics®为Loxooncology开发三款靶向CD3的双特异抗体，该交易总金额高达16亿美元。除与Lilly合作外，Merus还与incyte和国内的贝达，先声医药达成合作协议。 Biclonics®采用了共同的轻链防止双特异抗体的轻链和重链的错配，同时为了防止两个重链形成同源二聚体，两个重链的CH3进行氨基酸突变形成正负电荷（DEKK突变：一条重链上为D351，E368突变，另外一条重链上K351，K366突变），经过正负电荷改造后，双特异抗体的纯度可以达到99%；经过改造后，双特异抗体Fc的Tm值降低到69.5°C，而ZW（zymework）和EW-RVT-平台的抗体Fc的Tm值在80左右，接近天然的抗体。在Biclonics®平台的基础上，Merus科学家又开发了可以结合三个靶点的Triclonics™平台，该平台结合靶点的形式可以是2+1或者是1+1+1。与双特异抗体平台相似，该平台同样采用了共同轻链防止重链与轻链的错配；为了防止重链错配，采用了DEKK突变。本次与吉利德的合作是基于Triclonics™平台展开的第一个对外合作。图片来源：Merus官网 Merus的研发管线包括多个双抗，其中EGFR/LGR5双抗Petosemtamab (MCLA-158)、HER2/HER3双抗Zenocutuzumab (MCLA-128)、EGFR/c-MET双抗（MCLA-129)进展较快，均处于临床1/2期阶段。图片来源：Merus官网Petosemtamab (MCLA-158)MCLA-158抗体，也称为Petosemtamab，是一种双特异性抗体，靶向EGFR和LGR5。它临床前完全采用了类器官模型进行药物筛选，在早期阶段利用类器官快速筛选出潜在诊断标志物（Biomaker） KRAS突变并获得FDA批准临床实验，是目前基于类器官数据获批的领先药物。MCLA-158作为一种强效的癌类器官生长拮抗剂，在一些癌症临床前模型中，它可以阻止癌细胞的转移和生长，包括转移性结直肠癌、晚期头颈部鳞状细胞癌、食管腺癌和胃腺癌。MCLA-158于2018年在欧洲国家获得了CTA审批与FDA的IND审批，在2023年首次获得了FDA 授予其用于头颈部鳞状细胞癌患者快速通道的资格，目前处于临床2期，并有望和Keytruda®联用开展一项前线临床3期研究。Zenocutuzumab (MCLA-128)Zenocutuzumab是一款可以同时与HER2和HER3受体相结合的双特异性抗体，它可以阻止HER2和HER3形成二聚体，从而阻断神经调节蛋白的信号传导，因此它可能对NRG1阳性癌症特别有效。在临床前研究中，zenocutuzumab通过有效地抑制HER2/HER3二聚体的形成，从而抑制致癌信号通路、遏制肿瘤细胞的增殖和存活。此外，这种抗体还具有增强抗体依赖性细胞介导的细胞毒性（ADCC）的作用，从而提高免疫细胞对肿瘤的杀伤。去年7月，zenocutuzumab已获得美国FDA的突破性疗法认定，用于治疗先前接受过系统性治疗后仍出现进展的晚期不可切除或转移性NRG1融合阳性胰腺癌患者，这些患者没有令人满意的替代治疗方案。此次突破性疗法认定的授予得到了正在进行中的1/2期临床试验eNRGy和早期准入计划（EAP）的数据支持，这些试验正在评估zenocutuzumab单药治疗NRG1阳性癌症的安全性和抗肿瘤活性。来自eNRGy试验和EAP的数据在2021年和2022年的美国临床肿瘤学会（ASCO）年会上发布。ASCO摘要显示，在71名可评估的NRG1融合阳性癌症患者中，zenocutuzumab达到34%的客观缓解率（ORR），中位缓解持续时间为9.1个月。在非小细胞肺癌、胰腺癌、乳腺癌、胆管癌患者中均观察到缓解病例。MCLA-129MCLA-129 是一种 ADCC 增强型双特异性 IgG1 Biclonics®抗体，特异性的靶向 EGFR 和 c-Met，不仅能够克服 c-Met 信号依赖性 EGFR-TKI 的耐药机制，且与单独靶向 EGFR 的药物相比毒性更低。临床前试验表明，与同为 EGFR/c-Met 双抗的埃万妥单抗相比，MCLA-129 的 ADCC/ADCP 活性效果相当或者更优。在 NSCLC 的 I/II 临床试验中也获得积极的结果，RP2D 为每 14 天 1500 mg，目前正在探索多剂量扩展队列的临床试验。MCLA-129由贝达药业引进国内，目前MCLA-129联合甲磺酸贝福替尼胶囊用于晚期非小细胞肺癌患者的1期临床研究正在进行中。参考来源：企业官网Camilla De Nardis, Linda J. A.Hendriks et al, A new approach for generating bispecific antibodiesbased on a common light chain format and the stable architecture of human immunoglobulinG1. JBC 2017Antonio Tapia-Galisteo et al. when three is not a crowd: trispecific antibodies for enhanced cancer immunotherapy. Theranostics (2023)【智药研习社近期直播预告】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~

引进/卖出临床2期并购免疫疗法

2024-03-06

·Business Wire

Non-Small-Cell Lung Cancer (NSCLC) Pipeline Landscape Report 2024: Comprehensive Insights About 100+ Companies and 120+ Pipeline Drugs - ResearchAndMarkets.com

DUBLIN--( BUSINESS WIRE )--The "Non-Small-Cell Lung cancer (NSCLC) - Pipeline Insight, 2024" clinical trials has been added to ResearchAndMarkets.com's offering. This report provides comprehensive insights about 100+ companies and 120+ pipeline drugs in Non-Small-Cell Lung cancer (NSCLC) pipeline landscape. It covers the pipeline drug profiles, including clinical and nonclinical stage products. It also covers the therapeutics assessment by product type, stage, route of administration, and molecule type. It further highlights the inactive pipeline products in this space. The reportoutlays comprehensive insights of present scenario and growth prospects across the indication. A detailed picture of the Non-Small-Cell Lung cancer (NSCLC) pipeline landscape is provided which includes the disease overview and Non-Small-Cell Lung cancer (NSCLC) treatment guidelines. The assessment part of the report embraces, in depth Non-Small-Cell Lung cancer (NSCLC) commercial assessment and clinical assessment of the pipeline products under development. In the report, detailed description of the drug is given which includes mechanism of action of the drug, clinical studies, NDA approvals (if any), and product development activities comprising the technology, Non-Small-Cell Lung cancer (NSCLC) collaborations, licensing, mergers and acquisition, funding, designations and other product related details. Report Highlights The companies and academics are working to assess challenges and seek opportunities that could influence Non-Small-Cell Lung cancer (NSCLC) R&D. The therapies under development are focused on novel approaches to treat/improve Non-Small-Cell Lung cancer (NSCLC) . Non-Small-Cell Lung cancer (NSCLC) Emerging Drugs Chapters This segment of the Non-Small-Cell Lung cancer (NSCLC) report encloses its detailed analysis of various drugs in different stages of clinical development, including phase II, I, preclinical and Discovery. It also helps to understand clinical trial details, expressive pharmacological action, agreements and collaborations, and the latest news and press releases. Non-Small-Cell Lung cancer (NSCLC) Emerging Drugs V940: Merck Sharp & Dohme LLC V940 is designed to stimulate an immune response by generating specific T cell responses based on the unique mutational signature of a patient's tumor. It is a novel investigational messenger ribonucleic acid (mRNA)-based personalized cancer vaccine consisting of a single synthetic mRNA coding for up to 34 neoantigens that is designed and produced based on the unique mutational signature of the DNA sequence of the patient's tumor. Upon administration into the body, the algorithmically derived and RNA-encoded neoantigen sequences are endogenously translated and undergo natural cellular antigen processing and presentation, a key step in adaptive immunity. The drug is in Phase III stage for the treatment of NSCLC. QL1706: Qilu Pharmaceutical Co., Ltd. QL1706 is an investigational bifunctional antibody with additional anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody could increase the anti-tumor effect of anti-programmed cell death 1 (PD-1) antibody. QL1706 is a novel dual immune checkpoint blockade containing a mixture of anti-PD-1 IgG4 and anti-CTLA4 IgG1 antibodies produced by a single cell line. The drug is in Phase III stage for the treatment of NSCLC. Zenocutuzumab (MCLA-128): Merus N.V. Zenocutuzumab (MCLA-128; Zeno) is a Biclonics antibody that overcomes HER3 mediated NRG1 (or NRG1 fusion) signaling in tumor cells. Zeno docks on HER2, then binds to and blocks the NRG1 fusion-HER3 interaction and HER3 heterodimerization with HER2. It has a dual mechanism against cancer, as it prevents NRG1 fusions from binding to the protein HER3 and it blocks the interaction of HER3 with HER2, which the cancer cells depend on to survive and multiply. Currently, the drug is in Phase II stage for the treatment of NSCLC. ZW49: Zymeworks BC Inc. ZW49 (zanidatamab zovodotin) is a bispecific anti-HER2 ADC that is based on the same antibody framework as ZW25 but armed with a cytotoxic payload. A biparatopic (targeting two different non-overlapping epitopes on ERBB2, on extracellular domains 2 (ECD2) and 4 (ECD4). ZW25 is an anti-HER2 biparatopic antibody which binds to the same domains as trastuzumab and pertuzumab. ZW25 simultaneously binds two distinct sites on HER2, a protein expressed on many types of cancer cells. This unique design results in multiple mechanisms of action, including dual HER2 signal blockade, increased antibody binding, receptor clustering, and removal of HER2 from the cell surface, and potent e?ector function. ZW49 is in Phase I of clinical trials for the treatment of non-small cell lung cancer. Non-Small-Cell Lung cancer (NSCLC): Pipeline Development Activities The report provides insights into different therapeutic candidates in phase II, I, preclinical and discovery stage. It also analyses Non-Small-Cell Lung cancer (NSCLC) therapeutic drugs key players involved in developing key drugs. Pipeline Development Activities The report covers the detailed information of collaborations, acquisition and merger, licensing along with a thorough therapeutic assessment of emerging Non-Small-Cell Lung cancer (NSCLC) drugs. Non-Small-Cell Lung cancer (NSCLC) : Therapeutic Assessment Major Players in Non-Small-Cell Lung cancer (NSCLC) There are approx. 100+ key companies which are developing the therapies for Non-Small-Cell Lung cancer (NSCLC). The companies which have their Non-Small-Cell Lung cancer (NSCLC) drug candidates in the most advanced stage, i.e. Phase III include, Merck Sharp & Dohme LLC. Phases Late stage products (Phase III) Mid-stage products (Phase II) Early-stage product (Phase I) along with the details of Pre-clinical and Discovery stage candidates Discontinued & Inactive candidates Route of Administration Products have been categorized under various ROAs such as Oral Intravenous Subcutaneous Parenteral Topical Molecule Type Products have been categorized under various Molecule types such as Recombinant fusion proteins Small molecule Monoclonal antibody Peptide Polymer Gene therapy Product Type Non-Small-Cell Lung cancer (NSCLC) Report Insights Non-Small-Cell Lung cancer (NSCLC) Pipeline Analysis Therapeutic Assessment Unmet Needs Impact of Drugs Non-Small-Cell Lung cancer (NSCLC) Report Assessment Pipeline Product Profiles Therapeutic Assessment Pipeline Assessment Inactive drugs assessment Unmet Needs Key Players Merck Sharp & Dohme LLC Suzhou Puhe Pharmaceutical Technology Co., LTD Merus N.V. Zymeworks BC Inc. Cytos Biotechnology Exelixis ProfoundBio US Co. Beijing Pearl Biotechnology Limited Liability Company Pfizer OncoResponse, Inc. Next Point Therapeutics, Inc. Light Chain Bioscience - Novimmune SA Medolution Ltd. Immunitas Therapeutics Shanghai Henlius Biotech Key Products V940 YK-029A Zenocutuzumab (MCLA-128) ZW49 CMP 001 XL092 PRO1184 PLB1001 PF-07257876 OR2805 NPX267 NI-1801 Keynatinib IMT-009 HLX301 For more information about this clinical trials report visit https://www.researchandmarkets.com/r/w14gce About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends.

临床1期免疫疗法临床2期临床3期ASCO会议