更新于：2024-05-01

NEGF2

中期因子

更新于：2024-05-01

基本信息

别名

Amphiregulin-associated protein、ARAP、FLJ27379

+ [9]

简介

Secreted protein that functions as cytokine and growth factor and mediates its signal through cell-surface proteoglycan and non-proteoglycan receptors (PubMed:18469519, PubMed:12573468, PubMed:12122009, PubMed:10212223, PubMed:24458438, PubMed:15466886, PubMed:12084985, PubMed:10772929). Binds cell-surface proteoglycan receptors via their chondroitin sulfate (CS) groups (PubMed:12084985, PubMed:10212223). Thereby regulates many processes like inflammatory response, cell proliferation, cell adhesion, cell growth, cell survival, tissue regeneration, cell differentiation and cell migration (PubMed:12573468, PubMed:12122009, PubMed:10212223, PubMed:10683378, PubMed:24458438, PubMed:22323540, PubMed:12084985, PubMed:15466886, PubMed:10772929). Participates in inflammatory processes by exerting two different activities. Firstly, mediates neutrophils and macrophages recruitment to the sites of inflammation both by direct action by cooperating namely with ITGB2 via LRP1 and by inducing chemokine expression (PubMed:10683378, PubMed:24458438). This inflammation can be accompanied by epithelial cell survival and smooth muscle cell migration after renal and vessel damage, respectively (PubMed:10683378). Secondly, suppresses the development of tolerogenic dendric cells thereby inhibiting the differentiation of regulatory T cells and also promote T cell expansion through NFAT signaling and Th1 cell differentiation (PubMed:22323540). Promotes tissue regeneration after injury or trauma. After heart damage negatively regulates the recruitment of inflammatory cells and mediates cell survival through activation of anti-apoptotic signaling pathways via MAPKs and AKT pathways through the activation of angiogenesis (By similarity). Also facilitates liver regeneration as well as bone repair by recruiting macrophage at trauma site and by promoting cartilage development by facilitating chondrocyte differentiation (By similarity). Plays a role in brain by promoting neural precursor cells survival and growth through interaction with heparan sulfate proteoglycans (By similarity). Binds PTPRZ1 and promotes neuronal migration and embryonic neurons survival (PubMed:10212223). Binds SDC3 or GPC2 and mediates neurite outgrowth and cell adhesion (PubMed:12084985, PubMed:1768439). Binds chondroitin sulfate E and heparin leading to inhibition of neuronal cell adhesion induced by binding with GPC2 (PubMed:12084985). Binds CSPG5 and promotes elongation of oligodendroglial precursor-like cells (By similarity). Also binds ITGA6:ITGB1 complex; this interaction mediates MDK-induced neurite outgrowth (PubMed:15466886, PubMed:1768439). Binds LRP1; promotes neuronal survival (PubMed:10772929). Binds ITGA4:ITGB1 complex; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation (PubMed:15466886). Binds anaplastic lymphoma kinase (ALK) which induces ALK activation and subsequent phosphorylation of the insulin receptor substrate (IRS1), followed by the activation of mitogen-activated protein kinase (MAPK) and PI3-kinase, and the induction of cell proliferation (PubMed:12122009). Promotes epithelial to mesenchymal transition through interaction with NOTCH2 (PubMed:18469519). During arteriogenesis, plays a role in vascular endothelial cell proliferation by inducing VEGFA expression and release which in turn induces nitric oxide synthase expression. Moreover activates vasodilation through nitric oxide synthase activation (By similarity). Negatively regulates bone formation in response to mechanical load by inhibiting Wnt/beta-catenin signaling in osteoblasts (By similarity). In addition plays a role in hippocampal development, working memory, auditory response, early fetal adrenal gland development and the female reproductive system (By similarity).

关联

项与 NEGF2 相关的药物

CMK-103

靶点

NEGF2

作用机制

NEGF2刺激剂 [+1]

在研机构

Anagenics Ltd.

原研机构

Anagenics Ltd.

在研适应症

心肌梗塞

非在研适应症-

最高研发阶段临床阶段不明

首次获批国家/地区-

首次获批日期1800-01-20

Target MDK SSOs(Lyramid)

靶向MDK SSOs(Lyramid)

靶点

NEGF2

作用机制

NEGF2抑制剂

在研机构

Lyramid Ltd.

原研机构

Lyramid 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

hu91

靶点

NEGF2

作用机制

NEGF2抑制剂

在研机构

Anagenics Ltd.

原研机构

Anagenics Ltd.

在研适应症

肿瘤 [+1]

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

100 项与 NEGF2 相关的临床结果

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100 项与 NEGF2 相关的转化医学

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0 项与 NEGF2 相关的专利（医药）

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1,084

项与 NEGF2 相关的文献（医药）

2024-02-13·Cell cycle (Georgetown, Tex.)

B-cell ALL with SOX11 gene amplification associates with a worse outcome.

Article

作者: George Angelakakis ; Mallika Varkhedi ; Toriana R Dabkowski ; Michael J Diaz ; Michelle Yeagley ; George Blanck

Copy number variation (CNV) of certain genes in pediatric Acute Lymphoblastic Leukemia (ALL) impacts gene expression levels. Here, we aimed to investigate the potential prognostic utility of CNVs in pediatric B-ALL and T-ALL. Using genomics files representing cases from the TARGET-ALL-P2 dataset, genes commonly involved in ALL development were analyzed for CNVs. Case IDs representing increased copy numbers for SOX11, PDGFRB, and MDK represented a worse overall survival probability specifically for B-ALL (logrank p=0.021, p=0.0052, p=0.019, respectively). These data support the continued investigation of using CNVs for clinical prognostic biomarkers for pediatric B-ALL.

2024-02-12·American journal of physiology. Cell physiology

Elucidation of Pericholangitis and Periductal Fibrosis in Cholestatic Liver diseases via Extracellular Vesicles released by Polarized Biliary Epithelial cells.

Article

作者: Keita Maki ; Tomohiro Katsumi ; Takumi Hanatani ; Fumi Uchiyama ; Fumiya Suzuki ; Kyoko Hoshikawa ; Hiroaki Haga ; Takafumi Saito ; Yoshiyuki Ueno

Cholestatic liver diseases causes inflammation and fibrosis around bile ducts. However, the pathological mechanism has not been elucidated. Extracellular vesicles (EVs) are released from both the basolateral and apical sides of polarized biliary epithelial cells. We aimed to investigate the possibility that EVs released from the basolateral sides of biliary epithelial cells by bile acid stimulation induce inflammatory cells and fibrosis around bile ducts, and it may be involved in the pathogenesis of cholestatic liver disease. Human biliary epithelial cells (H69) were grown on cell culture inserts and stimulated with chenodeoxycholic acid + IFNγ. Human THP-1-derived M1-macrophages, LX-2 cells, and KMST-6 cells were treated with the extracted basolateral EVs, and inflammatory cytokines and fibrosis markers were detected by RT-PCR. Highly expressed proteins from stimulated EVs were identified, and M1-macrophages, LX-2, KMST-6 were treated with these recombinant proteins. Stimulated EVs increased the expression of TNF, IL-1β, and IL-6 in M1-macrophages, TGF-β in LX-2 and KMST-6 compared with the corresponding expression levels in unstimulated EVs. Nucleophosmin, nucleolin, and midkine levels were increased in EVs from stimulated cells compared with protein expression in EVs from unstimulated cells. Leukocyte cell-derived chemotaxin-2 (LECT2) is highly expressed only in EVs from stimulated cells. Stimulation of M1- macrophages with recombinant nucleophosmin, nucleolin, and midkine significantly increased the expression of inflammatory cytokines. Stimulation of LX-2 and KMST-6 with recombinant LECT2 significantly increased the expression of fibrotic markers. These results suggest that basolateral EVs are involved in the development of pericholangitis and periductal fibrosis in cholestatic liver diseases.

2024-02-03·BMC cardiovascular disorders

Exploration of neuron heterogeneity in human heart failure with dilated cardiomyopathy through single-cell RNA sequencing analysis.

Article

作者: Yu-Hui Cui ; Chun-Rong Wu ; Dan Xu ; Jian-Guo Tang

OBJECTIVE:

We aimed to explore the heterogeneity of neurons in heart failure with dilated cardiomyopathy (DCM).

METHODS:

Single-cell RNA sequencing (scRNA-seq) data of patients with DCM and chronic heart failure and healthy samples from GSE183852 dataset were downloaded from NCBI Gene Expression Omnibus, in which neuron data were extracted for investigation. Cell clustering analysis, differential expression analysis, trajectory analysis, and cell communication analysis were performed, and highly expressed genes in neurons from patients were used to construct a protein-protein interaction (PPI) network and validated by GSE120895 dataset.

RESULTS:

Neurons were divided into six subclusters involved in various biological processes and each subcluster owned its specific cell communication pathways. Neurons were differentiated into two branches along the pseudotime, one of which was differentiated into mature neurons, whereas another tended to be involved in the immune and inflammation response. Genes exhibited branch-specific differential expression patterns. FLNA, ITGA6, ITGA1, and MDK interacted more with other gene-product proteins in the PPI network. The differential expression of FLNA between DCM and control was validated.

CONCLUSION:

Neurons have significant heterogeneity in heart failure with DCM, and may be involved in the immune and inflammation response to heart failure.

项与 NEGF2 相关的新闻（医药）

2023-04-11

·World Pharma News

How cancer evades immune system detection and spreads

A research team led by the National Cancer Centre Singapore (NCCS) with members from Duke-NUS Medical School, KK Women and Childrens Hospital, A*STAR's Singapore Immunology Network (SIgN), the University of Southampton and the Alan Turing Institute, has discovered how cancer evades the immune system and metastasises in the body, and explores how to shut down this dangerous feature. How cancer cells escaped detection and destruction by the immune system was previously unknown, with many working to better understand it over the last few years. This latest breakthrough discovery, published in the high impact scientific journal Nature Communications on 27 March 2023, has implications for the development of novel strategies for cancer treatment. The immune system searches and destroys abnormal cells such as cancer cells. However, in some instances, cancer cells avoid being detected and killed by the immune system and are able to develop and spread more easily. Metastasis, a process when cancer cells break away from the primary tumour and form in other parts of the body, makes cancer harder to treat and results in poorer prognosis. For this reason, the team decided to investigate early onset of metastasis which typically occurs when cancer cells are detected in lymph nodes near the primary tumour. "Like an unethical employer that forces their employees to work continuously, cancer forces the immune cells to work overtime and become exhausted, rendering them incapable of functioning normally," said Professor Gopal Iyer, senior author of the study and Head and Senior Consultant, Department of Head and Neck Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and NCCS. "Using a treatment to alleviate stress on immune cells, we found that immune cells were able to kill cancer cells more effectively. Still, just like some employees who are too burnt out to work properly even with a bonus, some immune cells were seen to remain exhausted even after treatment, which is how cancer may not be detected and effectively destroyed by the immune system." Uncovering cancer immune system suppression: A three-part investigation As the basis of their investigation, the team profiled primary and metastatic lymph node tumours from 14 patients with head and neck squamous cell cancers, using single cell RNA sequencing. They found pre-metastatic cells within the primary tumours with the capacity to metastasise to the lymph nodes. They also found that a substantial proportion of CD8+ cells, a key component of the immune system that searches and kills abnormal cells such as cancer, were exhausted and unable to perform their protective role. This occurred when the immune cells were repeatedly exposed to cancer and unable to eliminate it. Next, the team identified and targeted pathways that exclusively affected cancer cells, immune cells, as well as pathways that cancer cells utilise to negatively influence immune cells, and were able to prevent some cancer spread and rejuvenate immune cells. However, despite these promising results, cancer cells continued to show their ability to escape immune surveillance. Using a mouse model, engrafted with pre-metastatic cancer cells, the team analysed a subgroup of CD8+ T cells expressing Midkine (MDK) receptors. One group in the model was treated with anti-PD1, while the other was a control arm. There was an increase in exhausted MDK-receptor expressing CD8+ T cells even after anti-PD1 treatment, suggesting that the MDK-signalling pathway instigates immune suppression that undoes the effects of anti-PD1 treatment. Taken together, the results implicate MDK-signalling as a pathway which pre-metastatic cancer cells use to evade CD8-mediated immune surveillance. It also explains why some patients do not respond as well as others to anti-PD1 therapy. Finding solutions to improve treatment outcomes "Our investigations indicate that we can use multiple pathways to effectively treat cancer - by targeting cancer cells, the immune system and using existing therapies to counter immune system evasion by cancer cells. We know we need an increased arsenal of weapons to use against cancer and have to put it together to improve treatment outcomes," said Professor Iyer, who is also head of the Division of Medical Sciences at NCCS. Along with exploiting the targets found in their research, the team plans to identify therapies that they can combine with anti-PD1 therapy to successfully counter CD8+ T cells expressing MDK-receptors. Quah HS, Cao EY, Suteja L, Li CH, Leong HS, Chong FT, Gupta S, Arcinas C, Ouyang JF, Ang V, Celhar T, Zhao Y, Tay HC, Chan J, Takahashi T, Tan DSW, Biswas SK, Rackham OJL, Iyer NG. Single cell analysis in head and neck cancer reveals potential immune evasion mechanisms during early metastasis. Nat Commun. 2023 Mar 27;14(1):1680. doi: 10.1038/s41467-023-37379-y

免疫疗法细胞疗法

2022-11-20

·药明康德

癌症疫苗提高结直肠癌患者总生存期三倍！创新疗法有效缓解PD-1耐药… | 一周盘点

▎药明康德内容团队编辑本期看点1. 玻璃体内注射的双重基因疗法4D-150治疗湿性年龄相关性黄斑变性（AMD），可减少眼内抗VEGF注射需求患者96.7%的年化注射率。2. 突变柠檬酸脱氢酶-1（mIDH1）抑制剂olutasidenib治疗血液癌症的早期临床数据亮眼，PDUFA的预计日期定为2023年2月15日。3. 潜在“first-in-class”的新型放射增敏剂NBTXR3的联合疗法效果亮眼，具有扩展到任何可以通过放疗治疗的实体肿瘤和任何联合治疗方案的潜力。4. 个体化癌症疫苗GRANITE联合免疫检查点抑制剂，使微卫星稳定型结直肠癌患者的总生存期翻3倍。药明康德内容团队整理4D-150：公布1b/2a期临床试验的中期数据4D Molecular Therapeutics公司公布了其玻璃体内注射的双重基因疗法4D-150用于治疗湿性AMD的早期临床数据。湿性AMD是一种影响视网膜中央黄斑部的病症，主要由脉络膜新生血管所导致，即在黄斑部有不正常的血管增生。4D-150由表达阿柏西普和抗VEGF-C的RNAi有效载荷以及能够在玻璃体内进行递送的专有载体R100组成，能够抑制4种血管生成因子：VEGFA、B、C和PlGF。新闻稿指出，4D-150是首款旨在抑制驱动血管生成的所有四种VEGF相关分子的视网膜基因疗法。此次公布的数据显示，玻璃体内注射4D-150后，入组前12个月的平均年化抗VEGF注射频率约为11次的高需求患者的年化抗VEGF注射率降低了96.7%，80%的患者在4D-150给药后长达10个月内未接受任何补充阿柏西普注射。截至目前，4D-150的安全性和耐受性良好，未报告有临床意义的眼内炎症或眼压过低。Olutasidenib：公布1/2期临床试验数据Rigel Pharmaceuticals公司公布了在研小分子mIDH1抑制剂olutasidenib单药或与阿扎胞苷（azacitidine）联合治疗复发/难治性mIDH1急性髓系白血病（AML）或骨髓增生异常综合征（MDS）的早期临床数据。IDH1是所有细胞正常代谢需要的一种天然酶，当发生突变时，它的活性可促进血液恶性肿瘤和实体瘤的发生。据统计，6-9%的AML患者携带IDH1突变。Olutasidenib旨在选择性结合并抑制突变的IDH1酶，有可能通过降低2-羟基戊二酸（2-HG）水平和恢复正常的细胞分化而为患者提供治疗益处。此次公布的数据显示，在接受联合治疗的患者中，初治AML患者的总缓解率（ORR）为77%，完全缓解（CR）+CR伴部分血液学恢复缓解率（CR/CRh）为54%。在MDS队列中，9例有响应的患者中有4例实现了突变清除，单药治疗和联合治疗均观察到CR，其中联合治疗组的ORR为86%，CR率为57%。Olutasidenib在AML和MDS患者中均具有良好的耐受性，未发生剂量限制性毒性。总体而言，单药治疗和联合治疗组的不良事件相似且可控。新闻稿指出，olutasidenib的新药申请（NDA）正在接受美国FDA的审查，PDUFA的预计日期定为2023年2月15日。NBTXR3：公布1期临床试验数据Nanobiotix公司公布了其潜在“first-in-class”的新型放射增敏剂NBTXR3在放疗激活后接着使用PD-1抑制剂的1期临床试验的积极数据。NBTXR3由功能化二氧化铪（HfO2）纳米颗粒组成，经由一次性瘤内注射给药并通过放射疗法激活。它的物理作用机制为：旨在通过放疗激活，诱导被注射肿瘤内大量的肿瘤细胞死亡，随后触发适应性免疫反应和长期的抗癌记忆。得益于该物理作用机制，Nanobiotix公司认为NBTXR3可以扩展到任何可以通过放疗治疗的实体肿瘤和任何联合治疗方案中，特别是与免疫检查点抑制剂联合。此次公布的研究结果显示，该疗法组合是可行的且耐受性良好。在可评估的21例患者中，71.43%被观察到目标病灶相对于基线的客观缩小，其中42.86%患者的病灶客观缩小超过30%，38.1%患者的全身性疾病控制持续了超过6个月。71.43%（15例）患者对先前的抗PD-1治疗耐药，在这些患者中有10例观察到了肿瘤的消退。此前，NBTXR3曾获得美国FDA授予用于治疗局部晚期头颈部鳞状细胞癌患者的快速通道资格。GRANITE：公布1/2期临床试验的新数据Gritstone bio公司公布了其在研个体化癌症疫苗GRANITE联合免疫检查点抑制剂，作为一线维持疗法，以治疗晚期实体瘤患者的临床1/2期试验最新数据。这款癌症疫苗的设计首先从患者体内获取活检组织，对肿瘤进行测序，然后利用其专有的人工智能平台EDGE识别新抗原，再利用腺病毒载体（GRT-C901）和自我扩增mRNA载体（GRT-R902）递送筛选出的新抗原，旨在引发显著的T细胞反应，特别是CD8+细胞毒性T细胞。此次公布的新数据显示，在曾接受过至少2线疗法的转移性微卫星稳定型结直肠癌（MSS-CRC）患者群中，此组合疗法帮助病患达到分子缓解，中位总生存期（OS）超过22个月，是过去接受3线疗法MSS-CRC患者的3倍（中位OS仅6-7个月）。APN401：公布1b期临床试验的1例病例报告invIOs公司公布了其潜在“first-in-class”的细胞疗法APN401的1b期临床试验的1例病例报告。研究表明，Cbl-b也是一种免疫检查点，APN401可以通过使用siRNA暂时减少自体外周血单核细胞（PBMC）中的Cbl-b的表达来增强免疫反应。Cbl-b沉默的自体PBMC可以在大约24小时内完成制造并回输给患者。目前，已有1例先前接受过11线治疗的转移性阑尾癌患者的疾病稳定了超过六个月。CTX130：公布1期临床试验数据CRISPR Therapeutics公司公布了其细胞疗法CTX130用于治疗复发或难治性透明细胞肾细胞癌（RCC）的1期临床试验数据。CTX130是健康供体衍生的CRISPR/Cas9基因编辑的同种异体CAR-T细胞疗法，靶向CD70。CD70是一种在多种实体肿瘤和血液恶性肿瘤上表达的抗原。此次公布的数据显示，CTX130显示出可耐受的安全性，没有脱靶毒性，并具有令人鼓舞的抗肿瘤活性，1例患者实现了持久的CR。CTX130在经过大量预处理的RCC患者群体中的DCR为77%，观察到的最长疾病稳定持续时间为7.8个月，并且在数据截止时仍在持续。KYV-101：IND申请获得FDA许可KYV-101是一款处于临床阶段、靶向CD19的CAR-T细胞疗法，其特性尤其适用于治疗B细胞驱动的自身免疫性疾病，如狼疮性肾炎、系统性硬化症和炎性肌病。临床前研究证明，该疗法可在疾病模型的血液循环和组织中，诱导深度和完全的B细胞耗竭，产生显著疗效。TAC01-HER2：公布1/2期临床试验的新中期数据Triumvira Immunologics公司公布了其TAC-T细胞疗法TAC01-HER2用于人类表皮生长因子受体2（HER2）阳性实体肿瘤的1/2期临床试验数据。TAC01-HER2是一种新型的细胞疗法，由基因工程自体T细胞组成，该T细胞表达T细胞抗原偶联剂（TAC），并可识别HER2。该疗法使用了Triumvira Immunologics专有的TAC平台技术，能以不同于CAR-T和TCR-T细胞疗法的方式激活天然T细胞功能。新的中期数据表明，TAC01-HER2具有良好的耐受性，在两个更高剂量的队列（队列2和队列3）中观察到临床活性，队列3的DCR为67%（n=3）。此外，在队列2中观察到了持续的临床益处。Galinpepimut-S：公布1/2期临床试验数据SELLAS Life Sciences Group公司公布了其靶向WT1蛋白的潜在“first-in-class”肿瘤免疫治疗新药Galinpepimut-S联用PD-1抑制剂pembrolizumab用于WT1+复发或难治性铂耐药晚期转移性卵巢癌的早期临床数据。该药由4条多肽链构成，抗原表位多达25个，适用于全球范围内绝大多数人类白细胞组织相容性抗原（HLA）类型，能够激发自身免疫系统对WT1抗原强烈的免疫反应。研究结果显示，使用该组合疗法患者的ORR为6.3%，疾病控制率（DCR）为50.1%（在检查点抑制剂单药治疗的类似患者群体研究中，该数据为37.2%），中位总生存期（OS）为18.4个月（同上类似患者群体研究中，该数据为13.8个月），中位无进展生存期（PFS）为12周（同上类似患者群体研究中，该数据为8周）。此外，在PD-L1表达的患者中观察到了生存和疾病控制方面的获益。MDNA11：公布1/2期临床试验数据Medicenna Corp公司公布了其下一代长效IL-2超级激动剂MDNA11治疗晚期实体肿瘤的早期临床结果。MDNA11具有优秀的CD122（IL-2受体β）结合作用，而没有CD25（IL-2受体α）亲和力，从而能优先刺激癌症杀伤效应T细胞和NK细胞。在该研究中，MDNA11对抗癌免疫细胞的选择性和剂量依赖性刺激表明，其抗肿瘤活性可能会随着剂量的持续增加而增加。此外，新数据再次证实该候选药物有潜力克服IL-2疗法的主要安全性、药代动力学和药效学局限性。INBRX-109：公布1期临床试验的新数据Inhibrx公司公布了其四价死亡受体5（DR5）激动抗体INBRX-109用于治疗软骨肉瘤的1期临床试验的新数据。DR5是肿瘤坏死因子相关细胞凋亡诱导配体（TRAIL）的受体。正常细胞对DR5介导的细胞死亡不太敏感。INBRX-109旨在利用多种癌症类型中DR5激活诱导的肿瘤偏向性的直接细胞死亡。此次公布的数据显示，在33例可评估的患者中，观察到的DCR为87.9%，其中2例（6.1%）患者为部分缓解（PR），27例（81.8%）患者为SD。临床获益是持久的，14例患者的临床获益超过了6个月，最长的SD持续时间为20个月。截至目前，中位PFS为7.6个月。MP0317：公布1期临床试验数据Molecular Partners公司公布了其新型蛋白质药物MP0317治疗实体肿瘤的1期临床试验数据。由于第一代CD40激动剂具有潜在的全身性毒副作用，这类药物的开发面临着挑战。MP0317旨在通过同时结合免疫刺激物CD40以及一种在肿瘤内高度表达的成纤维细胞活化蛋白（FAP），特异性激活肿瘤微环境中的免疫细胞，从而解决此前CD40激动剂存在的局限性。此次公布的数据显示，MP0317的安全性和耐受性良好，尚未观察到剂量限制性CD40相关的全身毒性，也没有炎性细胞因子释放的迹象。此外，在肿瘤组织活检中观察到局部CD40的激活。SRK-181：公布1期临床试验数据Scholar Rock公司公布了其旨在克服晚期癌症患者对检查点治疗的耐药性的单克隆抗体SRK-181的1期概念验证试验数据。TGFβ1是在许多人类肿瘤类型中表达的主要TGFβ亚型。研究表明，TGFβ1是免疫抑制肿瘤微环境的关键贡献者。SRK-181是一种选择性的潜在的TGFβ1激活抑制剂，与抗PD-（L）1疗法联合使用时，有潜力克服检查点治疗耐药问题，同时可能避免其他非选择性TGFβ抑制方法存在的心脏毒性。此次公布的数据显示，所有剂量下的SRK-181通常都具有良好的耐受性，没有观察到剂量限制性毒性。此外，在PD-1抑制剂耐药的透明细胞肾细胞癌患者中观察到两例确认的PR。MDK-703：公布1期临床试验的初步数据Medikine公司公布了其开发的半衰期延长的IL-7类似物MDK-703在健康志愿者中的早期临床数据。MDK-703是一种免疫球蛋白Fc片段-肽融合蛋白，含有使用Medikine平台技术发现的IL-7 PEPTIKINE（细胞因子的肽模拟物）。MDK-703比其模拟的IL-7细胞因子小得多，在结构上与天然的细胞因子无关，不会产生中和天然IL-7的抗药物抗体（ADA），这是此前在IL-7制品应用于人体试验中时经常会观察到的问题。此次公布的结果显示，MDK-703肌肉注射剂量在健康受试者中是安全且耐受性良好的，并且对血液中的免疫细胞具有类似IL-7的作用。CFI-402411：公布1/2期临床试验数据Treadwell Therapeutics公司公布了其潜在“first-in-class”的造血祖细胞激酶1（HPK1）免疫调节小分子抑制剂CFI-402411单药或与PD-1抑制剂pembrolizumab联用治疗晚期实体肿瘤的早期临床数据。研究表明，抑制HPK1可激活T细胞、B细胞和树突状细胞。此次公布的数据显示，CFI-40241的安全性在临床上可控，暴露量随剂量成比例增加。31例疗效可评估的患者中，2例达到PR（目标病灶分别缩小了36%和81%），9例达到SD。CUE-101：公布1期临床试验的新数据Cue Biopharma公司公布了基于IL-2的先导生物制品CUE-101与PD-1抑制剂pembrolizumab联用作为一线疗法治疗患有复发性/转移性HPV+头颈部鳞状细胞癌（HNSCC）的1期临床数据。结果显示，该联合疗法的ORR为40%，临床获益率（CBR）为70%。此外，CUE-101继续显示出良好的耐受性。IK-175：公布1b期临床试验数据Ikena Oncology公司公布了IK-175单药或与PD-1抑制剂nivolumab联用治疗既往接受过免疫检查点抑制剂治疗后进展的尿路上皮癌患者的早期临床结果。IK-175通过抑制被称为芳烃受体（AHR）的癌症驱动转录因子并调节肿瘤微环境来治疗癌症。此次公布的数据显示，IK-175单药治疗的ORR为10%，DCR为20%，观察到1例确认的PR，目前缓解持续时间（DoR）达到了14.9个月，且还在持续缓解中。IK-175联用nivolumab的ORR为20%，DCR为40%。此外，IK-175的耐受性良好，具有可预测和可管理的安全性。JIN-A02：IND申请获得FDA许可JIN-A02”是J INTS BIO公司开发的新型第4代口服EGFR酪氨酸激酶抑制剂（TKI），具有高度的选择性，可有效对抗携带C797S双突变或三突变的非小细胞肺癌，并具有高脑渗透率和体内疗效。药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看）[1] Rigel Announces Publication of Early Clinical Data of Olutasidenib in The Lancet Haematology. Retrieved November 10, 2022, from https://www.rigel.com/investors/news-events/press-releases/detail/348/rigel-announces-publication-of-early-clinical-data-of[2] J INTS BIO, Novel Oral 4th Generation EGFR TKI 'JIN-A02' - Phase 1/2 IND approved by US FDA. Retrieved November 10, 2022, from https://www.prnewswire.com/news-releases/j-ints-bio-novel-oral-4th-generation-egfr-tki-jin-a02---phase-12-ind-approved-by-us-fda-301675174.html[3] Kyverna Therapeutics Announces FDA Clearance of IND for KYV-101, a Novel Fully Human CD19 CAR T-Cell Therapy to Treat Lupus Nephritis. Retrieved November 10, 2022, from https://kyvernatx.com/press-releases/kyverna-therapeutics-announces-fda-clearance-of-ind-for-kyv-101-a-novel-fully-human-cd19-car-t-cell-therapy-to-treat-lupus-nephritis/[4] NANOBIOTIX Reports Updated Phase 1 Anti-PD-1 Combination Data That May Support the Immune Stimulation Potential of Radioenhancer NBTXR3 at the 37th Annual Meeting of the Society for Immunotherapy of Cancer. Retrieved November 10, 2022, from https://ir.nanobiotix.com/news-releases/news-release-details/nanobiotix-reports-updated-phase-1-anti-pd-1-combination-data[5] invIOs presents positive patient data from ongoing Phase 1b trial of APN401 cell therapy in advanced solid tumors at SITC 2022. Retrieved November 10, 2022, from https://www.invios.com/press-release-invios-presents-positive-patient-data-from-ongoing-phase-1b-trial-of-apn401-cell-therapy-in-advanced-solid-tumors-at-sitc-2022/[6] SELLAS Announces Confirmatory Top-Line Data Showing Survival and Clinical Benefits Based on the Final Analysis of the Phase 1/2 Clinical Trial of Galinpepimut-S in Combination with Keytruda® (pembrolizumab) in Patients with WT1+ Platinum-Resistant Advanced Ovarian Cancer. Retrieved November 10, 2022, from https://www.sellaslifesciences.com/investors/news/News-Details/2022/SELLAS-Announces-Confirmatory-Top-Line-Data-Showing-Survival-and-Clinical-Benefits-Based-on-the-Final-Analysis-of-the-Phase-12-Clinical-Trial-of-Galinpepimut-S-in-Combination-with-Keytruda-pembrolizumab-in-Patients-with-WT1-Platinum-Resistant-Advance/default.aspx[7] Ikena Oncology Announces Initial Clinical Data from IK-175 Program in Urothelial Carcinoma. Retrieved November 10, 2022, from https://ir.ikenaoncology.com/news-releases/news-release-details/ikena-oncology-announces-initial-clinical-data-ik-175-program[8] Medicenna Presents Updated Clinical Data from Dose Escalation Portion of Phase 1/2 ABILITY Study of MDNA11 at the SITC Annual Meeting. Retrieved November 10, 2022, from https://ir.medicenna.com/news-releases/news-release-details/medicenna-presents-updated-clinical-data-dose-escalation-portion[9] Recent Phase 1 DRAGON Data Show SRK-181 Continues to be Well Tolerated with Early Indications of Efficacy. Retrieved November 10, 2022, from https://investors.scholarrock.com/news-releases/news-release-details/recent-phase-1-dragon-data-show-srk-181-continues-be-well[10] Medikine Presents Preliminary Results of a Single-Dose Phase 1 Healthy Subject Study of MDK-703, a Peptide-Based Mimetic of Interleukin-7 (IL-7). Retrieved November 10, 2022, from https://www.medikine.com/press-releases/medikine-initiates-first-clinical-trial-of-its-lead-program-an-interleukin-7-mimetic-952pw-xzaxl[11] Gritstone Announces Updated Overall Survival Results from GRANITE Phase 1/2 Study and Poster at SITC 2022. Retrieved November 10, 2022 from https://ir.gritstonebio.com/news-releases/news-release-details/gritstone-announces-updated-overall-survival-results-granite[12] Ongoing Phase 1 Trial of CUE-101 in Combination with KEYTRUDA(R) for Recurrent/Metastatic HPV+ Head and Neck Cancer at the Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting. Retrieved November 10, 2022 from https://www.cuebiopharma.com/investors-media/news/[13] CRISPR Therapeutics Presents Data at the Society for Immunotherapy of Cancer (SITC) 37th Annual Meeting. Retrieved November 10, 2022 from http://ir.crisprtx.com/news-releases/news-release-details/crispr-therapeutics-presents-data-society-immunotherapy-cancer[14] Triumvira Immunologics Announces Updated Data from Ongoing TACTIC‑2 Trial of TAC01-HER2 in Patients with HER2 Positive Solid Tumors. Retrieved November 11, 2022 from https://triumvira.com/triumvira-immunologics-announces-updated-data-from-ongoing-tactic%e2%80%912-trial-of-tac01-her2-in-patients-with-her2-positive-solid-tumors/[15] Treadwell Therapeutics Announces A Presentation at the 2022 SITC Annual Meeting Featuring a Clinical Trial Update on CFI-402411, a First-in-Class HPK1 inhibitor. Retrieved November 11, 2022 from https://treadwelltx.com/news/treadwell-therapeutics-announces-a-presentation-at-the-2022-sitc-annual-meeting-featuring-a-clinical-trial-update-on-cfi-402411-a-first-in-class-hpk1-inhibitor/[16] 4D Molecular Therapeutics Announces Interim Clinical Data from On-going Phase 1/2 Clinical Trial of Intravitreal 4D-150 for Wet Age-Related Macular Degeneration (wet AMD). Retrieved November 14, 2022 from https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4d-molecular-therapeutics-announces-interim-clinical-data-going[17] NANOBIOTIX Announces Recommended Phase 2 Dose for NBTXR3 in Pancreatic Cancer. Retrieved November 14, 2022 from https://ir.nanobiotix.com/news-releases/news-release-details/nanobiotix-announces-recommended-phase-2-dose-nbtxr3-pancreatic[18] Assembly Biosciences Doses First Subject in Phase 1a Clinical Trial to Evaluate Safety, Tolerability and Pharmacokinetic Profile of Investigational Next Generation Core Inhibitor ABI-4334. Retrieved November 14, 2022 from https://investor.assemblybio.com/news-releases/news-release-details/assembly-biosciences-doses-first-subject-phase-1a-clinical-trial[19] Enlivex Announces Dosing of the First Patient in Phase I/II Trial Evaluating Allocetra Alone and in Combination with a PD1 Checkpoint Inhibitor in Patients with Advanced Solid Tumors. Retrieved November 15, 2022 from https://enlivex.com/investor-relations/#latest-news[20] Kineta Announces FDA Acceptance of Investigational New Drug (IND) Application for KVA12123 for the Treatment of Advanced Solid Tumors. Retrieved November 15, 2022 from https://kinetabio.com/2022/11/15/kineta-announces-fda-acceptance-of-investigational-new-drug-ind-application-for-kva12123-for-the-treatment-of-advanced-solid-tumors/[21] Inhibrx Announces Updated Efficacy and Safety Data from the Expansion Cohorts in the Phase 1 Trial of INBRX-109 for the Treatment of Chondrosarcoma. Retrieved November 16, 2022 from https://inhibrx.investorroom.com/2022-11-16-Inhibrx-Announces-Updated-Efficacy-and-Safety-Data-from-the-Expansion-Cohorts-in-the-Phase-1-Trial-of-INBRX-109-for-the-Treatment-of-Chondrosarcoma免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

基因疗法临床结果疫苗临床2期

2022-07-24

·药明康德

一周盘点 | 鼻内给药病毒疫苗、肿瘤浸润淋巴细胞疗法、质粒DNA癌症疫苗的最新进展...

▎药明康德内容团队编辑近期，又有多种创新药物取得了早期进展，其中包括双G蛋白偶联受体激动剂、肿瘤浸润淋巴细胞（TIL）疗法、质粒DNA（pDNA）皮肤癌疫苗等新颖的疗法类型，值得关注。在今天这篇文章里，药明康德内容团队将结合公开资料，与读者分享过去一周中部分创新药物的早期临床进展。ART27.13：启动1b期第4个队列的招募开发机构：Artelo Biosciences疗法类型：双G蛋白偶联受体激动剂适应症：癌症相关厌食症和体重减轻Artelo Biosciences宣布，在研疗法ART27.13的癌症食欲恢复研究（CAReS）已完成前3个队列的入组，并将启动第4个队列的入组，从而完成该1b期临床试验的第一阶段。ART27.13是一种被认为是针对大麻素受体CB1和CB2的外周选择性双G蛋白偶联受体激动剂，具有增加患者食欲和食物摄入量的潜力。ART27.13最初由阿斯利康公司开发，目前已在5个1期临床研究（共包括200多名受试者）中进行探索，结果显示，健康受试者的体重在统计学上显著增加，且呈剂量依赖性。更重要的是，这种体重的变化与体液潴留无关，药物的分布可以在影响全身代谢的同时将中枢神经系统介导的毒性降至最低。癌症厌食症和恶病质综合征（CACS）影响了超过60%的晚期癌症患者。目前，尚无FDA、MHRA或EMA批准的CACS疗法，且2020 ASCO指南不建议将特定的药物干预作为护理标准。Artelo Biosciences正在推进ART27.13作为患有厌食症和体重减轻的癌症患者的支持性护理疗法，有望填补这一空白领域。MDK-703：首个临床试验开始给药开发机构：Medikine疗法类型：IL-7类似物适应症：实体瘤Medikine宣布，其开发的半衰期延长的白细胞介素7（IL-7）类似物MDK-703将在健康志愿者中进行研究，用于评估以安慰剂为对照，肌肉注射剂量递增的MDK-703单药的安全性、耐受性、药代动力学和药效学。目前，该临床试验已开始给药，预计将在2022年第四季度获得最初的试验结果。在1期临床试验完成后，Medikine将探索MDK-703在实体肿瘤中的效果。IL-7是一种对T细胞的发育和维持至关重要的细胞因子，包括增强记忆T细胞的生成、功能和存活。在肿瘤治疗中，单独使用IL-7或与其它免疫疗法结合使用均能提高药物临床响应的速度、深度和持久性。MDK-703是一种免疫球蛋白Fc片段-肽融合蛋白，含有使用Medikine平台技术发现的IL-7 PEPTIKINE（细胞因子的肽模拟物）。MDK-703比其模拟的IL-7细胞因子小得多，在结构上与天然的细胞因子无关。因此，除了具有IL-7的抗肿瘤特性外，MDK-703还具有免疫原性低，易于结合靶点和其他药理学特征的特点。此外，MDK-703不会产生中和天然IL-7的抗药物抗体（ADA），这是之前在IL-7制剂应用于人体试验中时经常会观察到的问题。ITI-3000：完成首例患者给药开发机构：Immunomic Therapeutics疗法类型：pDNA疫苗适应症：默克尔细胞癌（MCC）Immunomic Therapeutics宣布，其质粒DNA（pDNA）疫苗ITI-3000已开启针对MCC的1期临床试验并完成了首例患者给药。这项单中心研究正在华盛顿大学医学院和华盛顿州西雅图的弗雷德哈钦森癌症中心进行，旨在评估ITI-3000在已接受过手术的MCC患者中的安全性、耐受性和免疫原性。MCC是一种罕见的具有侵袭性的皮肤癌，通常由默克尔细胞多瘤病毒（MCPyV）引起。ITI-3000借助了该公司的研究通用细胞内靶向表达（UNITE）平台，将MCPyV大T抗原（LT）突变序列融合到了编码LAMP-1蛋白的基因序列中。这种溶酶体靶向技术已被证明能够增强抗原呈递并平衡免疫反应，尤其是ITI-3000激活的体内抗原特异性CD4+T细胞。POLB 001：开启临床试验开发机构：Poolbeg Pharma疗法类型：小分子免疫调节剂适应症：严重流感 Poolbeg Pharma宣布，已获得伦理和主管当局的批准，开始其开发的小分子免疫调节剂POLB 001的人体临床试验，旨在解决严重流感治疗领域中未被满足的需求。该临床试验活动将于2022年7月22日正式开始，旨在评估POLB 001在抑制脂多糖（LPS）引起的严重免疫反应方面的疗效。POLB 001是一种p38 MAPK抑制剂，可以选择性地抑制病毒感染（如流感）中过度的炎症反应，同时保持必要的免疫功能以对抗感染。这与其他类固醇类的免疫调节方法形成鲜明对比，其他类固醇类药物会同时影响有益的和破坏性的免疫反应。VK0214：重启临床试验开发机构：Viking Therapeutics疗法类型：小分子甲状腺激素β受体（TRβ）激动剂适应症：X连锁肾上腺脑白质营养不良（X-ALD） Viking Therapeutics宣布，在提交了其开发的小分子TRβ激动剂VK0214未显示出遗传毒性的证据后，FDA批准其重启临床试验，预计将在未来几周内恢复入组。该临床试验是一项针对患有肾上腺脊髓神经病（AMN）成年男性患者的多中心、随机、双盲、安慰剂对照研究，旨在评估VK0214的安全性和耐受性。X-ALD是一种罕见的致命代谢性疾病，由ABCD1基因突变引起，这种突变会导致肾上腺脑白质营养不良蛋白（ALDP）功能障碍。ALDP是一种重要的过氧化物酶转运体，当其功能发生障碍会阻止患者有效代谢某些脂肪酸，而这些脂肪酸的累积会导致大脑和神经细胞周围的保护屏障破裂（即脱髓鞘），进而引发认知障碍、运动能力下降，甚至死亡。AMN是X-ALD最常见的形式。目前，X-ALD尚无获批的治疗方法。VK0214是一种新型的口服小分子TRβ激动剂，已被FDA授予治疗X-ALD的孤儿药资格。临床前研究表明，TRβ可以调节ABCD2相关基因的表达，ABCD2能够编码一种称为肾上腺脑白质营养不良相关蛋白（ADLRP）的代偿转运体，通过增加ABCD2表达可以使特定脂肪酸水平恢复正常。OBX-115：IND申请获FDA批准开发机构：MD安德森癌症中心和Obsidian Therapeutics疗法类型：TIL疗法适应症：黑色素瘤 MD安德森癌症中心和Obsidian Therapeutics共同宣布FDA批准了OBX-115的IND申请，可开启1期临床试验。这项单臂、开放标签的1期研究将评估OBX-115单药治疗复发性的或此前接受过抗PD-1抗体疗法无效的转移性黑色素瘤成人患者的安全性和初步疗效。OBX-115是一种新型的经过工程改造的TIL疗法，附着了经过调节的膜结合IL-15，使治疗过程无需再伴随IL-2这种毒性较强的治疗。临床前数据表明，与未经工程改造的TIL相比，OBX-115的持久性和有效性均得到了改善，有潜力改善患有不同类型实体瘤的患者的临床结局。BLB-201：完成首例患者给药开发机构：Blue Lake Biotechnology疗法类型：呼吸道合胞病毒（RSV）疫苗适应症：预防老年人（>60岁）和儿科人群（<2年）的RSV相关急性疾病Blue Lake Biotechnology宣布完成了其鼻内给药的RSV疫苗BLB-201在1期临床试验中的首次给药。RSV是一种常见的高传染性呼吸道病毒，也是引起急性呼吸道疾病的主要原因之一，每年感染全球超过6400万人。尽管对于大多数人来说，RSV引起的症状类似于普通感冒，但对于婴儿、免疫功能低下者、患有慢性心脏疾病或肺部疾病者以及老年人来说，RSV可能会导致严重的疾病，甚至危及生命。此外，RSV会重复感染。目前，尚无针对RSV的预防性疫苗或抗病毒治疗获批。BLB-201是一种RSV候选疫苗，已获得FDA的快速通道资格，用于预防老年人（>60岁）和儿科人群（<2年）的RSV相关急性疾病。BLB-201的主要活性成分是表达RSV F蛋白的PIV5减毒株，并使用专有的PIV5载体，可以通过鼻腔给药诱导体液免疫和细胞免疫。这种给药方式可以提高儿科患者及对针头害怕的患者的接受度。临床前研究结果显示，BLB-201在各类动物模型中均能对RSV引起的感染具有保护作用。期待这些疗法在未来取得积极成果，早日为更多患者带来更多希望！参考资料：[1] Artelo Biosciences Completes Enrollment of the First Three Cohorts in its CAReS Study Evaluating ART27.13 for the Treatment of Cancer-Related Anorexia and Weight Loss. Retrieved July 19, 2022，from https://ir.artelobio.com/news-events/press-releases/detail/88/artelo-biosciences-completes-enrollment-of-the-first-three[2] Medikine Initiates First Clinical Trial of its Lead Program, an Interleukin-7 Mimetic, Under Management Team with Expertise in Next-Generation Cytokine Drug Discovery and Development. Retrieived July 19, 2022, from https://www.medikine.com/press-releases/medikine-initiates-first-clinical-trial-of-its-lead-program-an-interleukin-7-mimetic[3] Immunomic Therapeutics Announces First Patient Dosed in Phase I Clinical Trial of ITI-3000 pDNA Vaccine for the Treatment of Merkel Cell Carcinoma. Retrieived July 20, 2022, from https://www.immunomix.com/immunomic-therapeutics-announces-first-patient-dosed-in-phase-i-clinical-trial-of-iti-3000-pdna-vaccine-for-the-treatment-of-merkel-cell-carcinoma/[4] Major milestone reached as POLB 001 human challenge clinical trial ready to commence. Retrieived July 20, 2022, from https://polaris.brighterir.com/public/poolbeg_pharma/news/rns_widget_investors/story/xl85g9w[5] Viking Therapeutics Announces FDA Has Lifted Clinical Hold on Phase 1b Trial of VK0214 in Patients with X-ALD. Retrieived July 19, 2022, from http://ir.vikingtherapeutics.com/2022-07-19-Viking-Therapeutics-Announces-FDA-Has-Lifted-Clinical-Hold-on-Phase-1b-Trial-of-VK0214-in-Patients-with-X-ALD[6] MD Anderson and Obsidian Therapeutics announce FDA Clearance of IND application for novel TIL therapy OBX-115. Retrieived July 21, 2022, from https://obsidiantx.com/news-releases/md-anderson-and-obsidian-therapeutics-announce-fda-clearance-of-ind-application-for-novel-til-therapy-obx-115/[7] Blue Lake Biotechnology Announces First Participant Dosed in a Phase 1 Clinical Trial of Its BLB-201 Intranasal RSV Vaccine. Retrieived July 21, 2022, from https://www.biospace.com/article/releases/blue-lake-biotechnology-announces-first-participant-dosed-in-a-phase-1-clinical-trial-of-its-blb-201-intranasal-rsv-vaccine/免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

疫苗细胞疗法信使RNA基因疗法免疫疗法