更新于：2024-11-01

PTPN2

更新于：2024-11-01

基本信息

别名

protein tyrosine phosphatase non-receptor type 2、PTPN2、PTPT

+ [5]

简介

Non-receptor type tyrosine-specific phosphatase that dephosphorylates receptor protein tyrosine kinases including INSR, EGFR, CSF1R, PDGFR. Also dephosphorylates non-receptor protein tyrosine kinases like JAK1, JAK2, JAK3, Src family kinases, STAT1, STAT3 and STAT6 either in the nucleus or the cytoplasm. Negatively regulates numerous signaling pathways and biological processes like hematopoiesis, inflammatory response, cell proliferation and differentiation, and glucose homeostasis. Plays a multifaceted and important role in the development of the immune system. Functions in T-cell receptor signaling through dephosphorylation of FYN and LCK to control T-cells differentiation and activation. Dephosphorylates CSF1R, negatively regulating its downstream signaling and macrophage differentiation. Negatively regulates cytokine (IL2/interleukin-2 and interferon)-mediated signaling through dephosphorylation of the cytoplasmic kinases JAK1, JAK3 and their substrate STAT1, that propagate signaling downstream of the cytokine receptors. Also regulates the IL6/interleukin-6 and IL4/interleukin-4 cytokine signaling through dephosphorylation of STAT3 and STAT6 respectively. In addition to the immune system, it is involved in anchorage-dependent, negative regulation of EGF-stimulated cell growth. Activated by the integrin ITGA1/ITGB1, it dephosphorylates EGFR and negatively regulates EGF signaling. Dephosphorylates PDGFRB and negatively regulates platelet-derived growth factor receptor-beta signaling pathway and therefore cell proliferation. Negatively regulates tumor necrosis factor-mediated signaling downstream via MAPK through SRC dephosphorylation. May also regulate the hepatocyte growth factor receptor signaling pathway through dephosphorylation of the hepatocyte growth factor receptor MET. Also plays an important role in glucose homeostasis. For instance, negatively regulates the insulin receptor signaling pathway through the dephosphorylation of INSR and control gluconeogenesis and liver glucose production through negative regulation of the IL6 signaling pathways. May also bind DNA.

关联

项与 PTPN2 相关的药物

Osunprotafib

靶点

PTP1B x PTPN2

作用机制

PTP1B抑制剂 [+1]

在研机构

AbbVie, Inc. [+1]

原研机构

Calico LLC [+1]

在研适应症

晚期恶性实体瘤

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

Tegeprotafib

靶点

PTP1B x PTPN2

作用机制

PTP1B抑制剂 [+1]

在研机构

Calico LLC [+1]

原研机构

Calico LLC

在研适应症

晚期恶性实体瘤

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

PTPN1/2 inhibition(Nerio)

靶点

PTP1B x PTPN2

作用机制

PTP1B抑制剂 [+1]

在研机构

Boehringer Ingelheim GmbH [+1]

原研机构

Boehringer Ingelheim GmbH [+1]

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 PTPN2 相关的临床试验

NCT06188975 / AvailableN/A

Expanded Access to ABBV-CLS-484

This is an expanded access program (EAP) for eligible participants. This program is designed to provide access to ABBV-CLS-484 prior to approval by the local regulatory agency. Availability will depend on territory eligibility. A medical doctor must decide whether the potential benefit outweighs the risk of receiving an investigational therapy based on the individual patient's medical history and program eligibility criteria.

开始日期-

申办/合作机构

Calico LLC

NCT04777994 / Recruiting临床1期

A Phase 1, Multi-center, Open Label First-in-Human Study With ABBV-CLS-484 Alone and in Combination in Subjects With Locally Advanced or Metastatic Tumors

The study will assess the safety, PK, PD, and preliminary efficacy of ABBV-CLS-484 as monotherapy and in combination with a PD-1 targeting agent or with a or a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI).
The trial aims to establish a safe, tolerable, and efficacious dose of ABBV-CLS-484 as monotherapy and in combination. The study will be conducted in three parts. Part 1 Monotherapy Dose Escalation, Part 2 Combination Dose Escalation and Part 3 Dose Expansion (Monotherapy and Combination therapy).
Part 1, ABBV-CLS-484 will be administered alone in escalating dose levels to eligible subjects who have advanced solid tumors.
Part 2, ABBV-CLS-484 will be administered at escalating dose levels in combination with a PD-1 targeting agent or with a VEGFR TKI to eligible subjects who have advanced solid tumors.
Part 3, ABBV-CLS-484 will be administered alone as a monotherapy at the determined recommended dose in subjects with locally advanced or metastatic, relapsed or refractory head and neck squamous cell carcinoma (HNSCC), relapsed or refractory non-small cell lung cancer (NSCLC), and advanced clear cell renal cell carcinoma (ccRCC). ABBV-CLS-484 will also be administered at the determined recommended dose in combination with a PD-1 targeting or with a VEGFR TKI agent in subjects with locally advanced or metastatic, HNSCC, NSCLC, MSI-H tumors refractory to PD-1/PD-L1, and advanced ccRCC.

开始日期2021-03-09

申办/合作机构

AbbVie, Inc.

[+1]

NCT04417465 / Active, not recruiting临床1期

A Phase 1, Multi-center, Open Label First-in-Human Study With ABBV-CLS-579 Alone and in Combination in Subjects With Locally Advanced or Metastatic Tumors

The purpose of this study is to see how safe and effective ABBV-CLS-579 is when used alone and in combination with a PD-1 target agent or with a VEGF TKI.
ABBV-CLS-579 is an investigational drug being developed for the treatment of tumors.
The trial aims to establish a safe, tolerable, and efficacious dose of ABBV-CLS-579 as monotherapy and in combination. The study will be conducted in three parts. Part 1 Monotherapy Dose Escalation, Part 2 Combination Dose Escalation, and Part 3 Combination Dose Expansion.
Part 1, ABBV-CLS-579 will be administered alone in escalating dose levels to eligible subjects who have advanced solid tumors.
Part 2, ABBV-CLS-579 will be administered at escalating dose levels in combination with a PD-1 targeting agent to eligible subjects who have advanced solid tumors.
Part 3, ABBV-CLS-579 will be administered at the determined recommended dose in combination with a PD-1 target agent or with a VEGFR TKI in subjects with locally advanced or metastatic, relapsed or refractory head and neck squamous cell carcinoma (HNSCC), relapsed or refractory non-small cell lung cancer (NSCLC), and advanced clear cell renal cell carcinoma (ccRCC).
Adult participants with a diagnosis of some solid tumors for which no effective standard therapy exists or has failed will be enrolled. Participants will receive study treatment until disease progresses or discontinued.
There may be a higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the course of the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects, and completing questionnaires.

开始日期2020-06-03

申办/合作机构

AbbVie, Inc.

[+1]

100 项与 PTPN2 相关的临床结果

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100 项与 PTPN2 相关的转化医学

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0 项与 PTPN2 相关的专利（医药）

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812

项与 PTPN2 相关的文献（医药）

2025-01-01·Gene

Genetic variants in FCGR2A, PTPN2, VDR as predictive signatures of aggressive phenotypes in cerebral cavernous malformation

Article

作者: Salvio, Andreza L ; Trefilio, Luisa M ; Alves-Leon, Soniza V. ; de Souza, Jorge M. ; Fontes-Dantas, Fabrícia L. ; Galvão, Gustavo F ; Fontes-Dantas, Fabrícia L ; Alves-Leon, Soniza V ; de Souza, Jorge M ; Trefilio, Luisa M. ; da Silva, Elielson V. ; Salvio, Andreza L. ; Galvão, Gustavo F. ; da Silva, Elielson V

OBJECTIVEThe biological behavior of Cerebral Cavernous Malformation (CCM) is still controversial, lacking a clear-cut signature for a mechanistic explanation of lesion aggressiveness. In this study, we evaluated the predictive capacity of genetic variants concerning the aggressive behavior of CCM and their implications in biological processes.METHODSWe genotyped the variants in VDR^rs7975232, VDR^rs731236, VDR^rs11568820, PTPN2^rs72872125 and FCGR2A^rs1801274 genes using TaqMan Genotyping Assays in a cohort study with 103 patients, 42 of whom had close follow-up visits for 4 years, focusing on 2 main aspects of the disease: (1) symptomatic events, which included both intracranial bleeding or epilepsy, and (2) the onset of symptoms. The genotypes were correlated with the levels of several cytokines quantified in peripheral blood, measured using the x-MAP method.RESULTSWe report a novel observation that the PTPN2^rs72872125 CT and the VDR^rs7975232 CC genotype were independently associated with an asymptomatic phenotype. Additionally, PTPN2^rs72872125 CC genotype and serum level of GM-CSF could predict a diagnostic association with symptomatic phenotype in CCM patients, while the FCGR2A^rs1801274 GG genotype could predict a symptomatic event during follow-up. The study also found a correlation between VDR^r^s731236 AA and VDR^rs11568820 CC genotype to the time to the first symptomatic event.CONCLUSIONSThese genetic markers could pave the way for precision medicine strategies for CCM, enhancing patient outcomes by enabling customized therapeutic approaches.

2024-12-01·Cellular and Molecular Life Sciences

Fetal growth restriction and placental defects in obese mice are associated with impaired decidualisation: the role of increased leptin signalling modulators SOCS3 and PTPN2

Article

作者: Kelsey, Gavin ; Laniecka, Elżbieta ; Alvarez-Sanchez, Andrea ; Galvão, António M ; Molcan, Tomasz ; Walewska, Edyta ; Makowczenko, Karol G ; Perez-Garcia, Vicente ; Witek, Krzysztof

AbstractDecidualisation of the endometrium is a key event in early pregnancy, which enables embryo implantation. Importantly, the molecular processes impairing decidualisation in obese mothers are yet to be characterised. We hypothesise that impaired decidualisation in obese mice is mediated by the upregulation of leptin modulators, the suppressor of cytokine signalling 3 (SOCS3) and the protein tyrosine phosphatase non-receptor type 2 (PTPN2), together with the disruption of progesterone (P4)-signal transducer and activator of transcription (STAT3) signalling. After feeding mice with chow diet (CD) or high-fat diet (HFD) for 16 weeks, we confirmed the downregulation of P4 and oestradiol (E2) steroid receptors in decidua from embryonic day (E) 6.5 and decreased proliferation of stromal cells from HFD. In vitro decidualised mouse endometrial stromal cells (MESCs) and E6.5 deciduas from the HFD showed decreased expression of decidualisation markers, followed by the upregulation of SOCS3 and PTPN2 and decreased phosphorylation of STAT3. In vivo and in vitro leptin treatment of mice and MESCs mimicked the results observed in the obese model. The downregulation of Socs3 and Ptpn2 after siRNA transfection of MESCs from HFD mice restored the expression level of decidualisation markers. Finally, DIO mice placentas from E18.5 showed decreased labyrinth development and vascularisation and fetal growth restricted embryos. The present study revealed major defects in decidualisation in obese mice, characterised by altered uterine response to E2 and P4 steroid signalling. Importantly, altered hormonal response was associated with increased expression of leptin signalling modulators SOCS3 and PTPN2. Elevated levels of SOCS3 and PTPN2 were shown to molecularly affect decidualisation in obese mice, potentially disrupting the STAT3-PR regulatory molecular hub.

2024-11-01·European Journal of Medicinal Chemistry

Regulation of protein phosphorylation by PTPN2 and its small-molecule inhibitors/degraders as a potential disease treatment strategy

Review

作者: Wang, Wenmu ; Xie, Yishi ; Yang, Peng ; Kuang, Wenbin ; Song, Mingge ; Wang, Dawei

项与 PTPN2 相关的新闻（医药）

2024-10-08

·生物制品圈

福医大最新 | 环状mRNA(circRNA)个性化肝癌疫苗的研发成果

导读：癌症患者间新抗原差异是通用癌症疫苗/药物开发的一大难题，基于核酸的新抗原疫苗的开发是一种新的应对技术。体外转录（IVT）mRNA新抗原疫苗的代表性产品为BioNTech和罗氏子公司基因泰克合作开发的autogene cevumeran（BNT122），其他相似管线包括XH101、ABOR2014和LK101等。 2024年7月29日，福建医科大学刘小龙等人在MedComm（影响因子10.7）发表文章：Circular RNA-based neoantigen vaccine for hepatocellular carcinoma immunotherapy，他们开发了一种基于circRNA的肿瘤新抗原疫苗，通过表达肝癌新抗原Ptpn2_I383T，促进树突状细胞（DC）活化并增强DC诱导的T细胞活化，从而增强T细胞对肿瘤细胞的杀伤。这种基于circRNA技术的肿瘤新抗原疫苗在小鼠肿瘤模型表现出卓越的肿瘤治疗和预防，为实体瘤新抗原免疫疗法提供了新的选择和应用前景。 01 研究背景肿瘤新抗原(Neoantigens)是指只在肿瘤细胞表达，而在正常组织细胞中不表达的抗原分子。它们是由肿瘤细胞基因组突变、RNA剪接失调、翻译后修饰紊乱和病毒整合等机制产生的。肿瘤中的新抗原数量可高达成百上千甚至上万个，而每个患者的新抗原各不相同，呈现高度的个体差异性。最近，BioNTech开发了一款表达胰腺癌患者20种新抗原的个性化mRNA新抗原疫苗—BNT122，在手术切除后的胰腺患者中，与化疗和免疫检查点疗法联用时，有潜力地延缓了PDAC患者的复发。同时，国内多家mRNA公司在肿瘤新抗原mRNA疫苗研发方面也取得显著进展： ·XH101: 新合生物开发的靶向胃癌公共新抗原的治疗性肿瘤mRNA疫苗。从大量胃癌患者中筛选、预测、验证出的一段免疫原性强、覆盖度广的肿瘤公共新抗原序列。 ·ABOR2014：艾博生物与臻知医学合作开发的编码近20种肝癌抗原的治疗性肿瘤mRNA疫苗，该疫苗经肌肉注射后可诱导患者自身免疫系统恢复抗肿瘤能力，联合PD-1抑制剂进一步激活T细胞。 ·LK101：北京立康开发的一款基于新生抗原的个性化治疗性肿瘤mRNA疫苗，覆盖了数十个新生抗原靶点。利用编码肿瘤新生抗原的mRNA体外转染DC细胞，兼具了mRNA疫苗和DC疫苗的优势。 02 肿瘤新抗原circRNA疫苗的设计早在2022年，刘小龙团队在小鼠肝癌细胞系Hepa1-6中筛选并鉴定出七种可触发强烈免疫反应的突变编码肽，并且设计了一款由高免疫原性新抗原肽和临床级Poly（I：C）组成的肝癌肿瘤新抗原疫苗NeoVAC，可在HCC小鼠模型中产生强烈的抗肿瘤免疫反应。正是基于上述研究结果，刘小龙团队从七种筛选到的新抗原中选择免疫原性更显著的Ptpn2_I383T作为circRNA编码的肝癌新抗原（Neoantigen）。本研究采用2018年Daniel Anderson开发的具有自我剪接功能的I型内含子环化策略构建circRNA骨架序列，并将其克隆至PET-28a质粒载体上。按照体外转录（IVT）→DNase I酶切→试剂盒纯化→重新环化（GTP+55℃，15min）→RNase R富集circRNA→纯化circRNA工序，制备得到高纯度的circRNA，并且通过琼脂糖凝胶电泳、PCR及Sanger测序确认环化反应成功制备circRNA。在细胞水平，与LinRNA（线性mRNA）相比，circRNA表达荧光蛋白或者PTPN2新抗原的水平更高。 03 circRNA疫苗稳定性研究3.1 存储稳定性相比LinRNA，circRNA无游离末端，拥有更高的稳定性。线性mRNA（LinRNA）对RNase R极其敏感，而circRNA耐受RNase R的降解。在室温条件下放置，随着时间的推移，LinRNA表达活性会出现极其显著的下降，相比之下，circRNA表达活性下降更加缓慢。这些数据表明，circRNA比线性RNA更稳定、蛋白表达更持久。 3.2 表达稳定性小鼠尾静脉注射10ug circLuc LNP，活体成像系统显示circRNA主要靶向肝脏。共聚焦激光扫描显微镜显示Cy5 标记的 circRNA主要位于溶酶体。尾静脉注射LinGluc LNP或者CircGLuc LNP，LinGluc在注射第3天后表达出现显著下降，表达持续至第9天，相比之下，CircGLuc在注射第5天后表达出现显著下降，表达持续至第11天。 04 circRNA体外免疫原性评估为增强多肽片段表达，研究人员采用三个多肽片段 3×PTPN2 的重复序列作为新抗原。CD80和CD86是两种重要的共刺激分子，主要由抗原呈递细胞（APCs）表达，对T细胞的激活和免疫反应起着关键作用。相比PBS或者CircGLuc对照组，转染circRNA3×PTPN2的DC细胞组，CD80、CD86及MHC 1表达明显增强，说明编码新抗原的circRNA疫苗明显促进DC细胞激活。将转染circRNA3×PTPN2的DC细胞与未激活的T细胞共同培养会显著增加CD25+或者CD69+活化T细胞比例，而且，T细胞分泌的IFN-γ/TNF-α细胞因子水平也明显增加。 circRNA3×PTPN2免疫小鼠脾脏的离体 IFN-γ ELISPOT 测定表明免疫小鼠体内触发有效的T细胞免疫反应。此外，circRNA3×PTPN2疫苗还展现出对 Hepa1-6 肿瘤细胞显著的杀伤能力。上述结果表明，circRNA3×PTPN2新抗原疫苗能够促进DC细胞成熟，刺激T细胞活化，从而增强T细胞介导的肿瘤细胞杀伤能力。 05 circRNA新抗原疫苗HCC治疗效果5.1 皮下HCC模型皮下注射Hepa1-6荷瘤小鼠模型，与LinRNA LNP相比，尾静脉注射circRNA3×PTPN2 LNP会更加显著的抑制肿瘤生长。值得注意的是，60%（3/5）小鼠的肿瘤完全消失，并且，这种肿瘤抑制作用呈现剂量依赖性。在circRNA3×PTPN2 LNP免疫组小鼠的肿瘤组织中，发现更多的浸润T细胞，诱导更多的肿瘤细胞死亡。 5.2 原位HCC模型在表达荧光素酶的Hepa1-6细胞的肝内肿瘤模型中，与PBS或者线性RNA对照组相比，注射circRNA3×PTPN2 LNP后，随着治疗时间的延长，肿瘤部位的荧光信号显著减低，最终，circRNA疫苗接种组80%的小鼠肝脏肿瘤完全消失，并且存活时间得到延伸。表征先天免疫反应的IL-6和TNF-α在circRNA疫苗接种组中也表现出更高的血清水平。在circRNA疫苗接种组，引流淋巴结中的成熟DC细胞比例更高，脾脏中的CD25 +和CD69 + T细胞比例更高，而且CD44+CD62L+ 中枢记忆 T 细胞比例也高。ELISPOT显示circRNA疫苗接种组小鼠脾脏分泌更多的IFN-γ，并且肿瘤组织中浸润T淋巴细胞更高。总的来说，circRNA新抗原疫苗在小鼠皮下或者原位肝癌模型中均可触发有效的先天免疫反应和适应性免疫反应，抑制肿瘤生长，延长小鼠存活时间。 06 circRNA新抗原疫苗预防效果在小鼠尾静脉间隔七天注射两次circRNA3×PTPN2 LNP，随后皮下注射Hepa1-6肝癌细胞，评估circRNA新抗原疫苗的免疫保护效果。与线性RNA或者PBS组相比，circRNA免疫小鼠体内的肿瘤受到更加显著的抑制，分泌IFN-γ的特异性浸润CD8+ T细胞比例更高。这些数据表明circRNA新抗原疫苗可触发有效的免疫反应预防肿瘤生长。 07 总结采用PIE策略（permuted intron‒exon）体外构建circRNA，可在circRNA骨架中插入较长的靶标蛋白编码序列。相比依赖帽结构翻译的线性mRNA来说，IRES介导的circRNA更加稳定，蛋白翻译持续时间更久。而且，circRNA本身携带的I型催化活性的内含子序列具有免疫原性，从而起到佐剂的作用。体细胞突变可以产生癌细胞特有的新抗原，而这些新抗原不存在于健康组织中。这一特性使它们成为开发免疫治疗策略的理想靶点。与多肽疫苗相比，circRNA具有更高的免疫原性，可以诱导更强大的先天免疫，使其成为一种有效的自我佐剂。与线性mRNA相比，circRNA在存储和蛋白表达稳定性方面更加卓越。这项工作开发的基于circRNA平台的肝癌新抗原疫苗在肿瘤小鼠模型中表现出非常有效的抗肿瘤效果，触发显著的先天免疫和细胞免疫反应。总之，这项工作充分证实基于circRNA的肿瘤疫苗拥有的巨大的临床转化潜力和独特的优势。在未来，随着circRNA制备工艺的成熟，circRNA肿瘤疫苗的开发会迎来新浪潮。参考文献 [1] Wang F, Cai G, Wang Y, Zhuang Q, Cai Z, Li Y, Gao S, Li F, Zhang C, Zhao B, Liu X. Circular RNA-based neoantigen vaccine for hepatocellular carcinoma immunotherapy. MedComm (2020). 2024 Jul 29;5(8):e667. doi: 10.1002/mco2.667. 识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所转载文章系出于天坛生物，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

疫苗信使RNA免疫疗法

2024-09-11

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Sci Trans Med丨夏伟梁、陆舜团队合作揭示PTPRT缺失增强非小细胞肺癌抗肿瘤免疫疗效

引言目前，免疫检查点抑制剂（immune checkpoint inhibitor, ICI）在晚期非小细胞肺癌患者临床实践中已广泛应用，但总体临床响应率有限【1, 2】。探索抗肿瘤免疫的机制和新靶点，并通过联合治疗提高ICI疗效是重要的研究方向。蛋白酪氨酸磷酸酶分为受体型和非受体型两类，既往研究发现SHP2，PTPN1和PTPN2等非受体型蛋白酪氨酸磷酸酶调控多种细胞因子信号通路和TCR信号通路，参与抗肿瘤免疫的调节【3, 4】。而受体型蛋白酪氨酸磷酸酶在抗肿瘤免疫中的功能和作用机制较少报道。 2024年9月4日，上海交通大学生物医学工程学院夏伟梁团队和上海交通大学医学院附属胸科医院陆舜团队合作在 Science Translational Medicine 上发表了题为PTPRT loss enhances anti-PD-1 therapy efficacy by regulation of STING pathway in non-small cell lung cancer 的研究论文。该研究首次发现并系统阐述了受体型蛋白酪氨酸磷酸酶PTPRT缺失通过调节STING通路增强免疫检查点抑制剂疗效的分子机制。在该研究中，研究团队通过对非小细胞肺癌公共数据库分析和临床样本验证，发现携带T 型受体蛋白酪氨酸磷酸酶（PTPRT）基因突变特别是磷酸酶片段突变的患者更能从ICI治疗中获益。此外，PTPRT蛋白表达阴性的患者也是ICI治疗的响应人群。由此提出肿瘤PTPRT缺失是独立于PD-L1表达的预测ICI疗效的新型生物标志物。研究团队通过转录组蛋白组测序、分子模拟和蛋白互作等实验阐明了分子机制：PTPRT 缺失型肿瘤表现出累积的 DNA 损伤、增加的胞质 DNA和更高的肿瘤突变负荷，间接激活STING通路。同时，鉴定出PTPRT去磷酸化的新底物为STING Y240位点。肿瘤PTPRT缺失提高了STING Y240位点酪氨酸磷酸化水平，抑制了STING的泛素化降解。研究团队进一步发现PTPRT缺失的肿瘤通过激活 STING通路分泌更多的I型干扰素和趋化因子，增加肿瘤微环境中CD8+ T细胞和NK细胞的浸润，使 “冷”肿瘤转“热”，增强了免疫检查点抑制剂在多种小鼠肿瘤模型中的治疗效果。图1 肿瘤PTPRT缺失改善肿瘤免疫微环境，抑制肿瘤增长（Credit: Science Translational Medicine） STING通路的激活在肿瘤免疫中是一把双刃剑：STING的激活不仅促进T细胞浸润和杀伤，同时也被证明诱导免疫抑制分子如PD-L1和IDO的表达，高剂量的STING激动剂可诱导T细胞凋亡5。STING蛋白在全身多种细胞中广泛表达，STING激动剂全身给药会诱导体内大量促炎因子的分泌，甚至引发细胞因子风暴6。基于 PTPRT 对 STING 的翻译后修饰机制，PTPRT 缺失通过延缓 STING蛋白的降解不会过度激活STING，也不上调免疫抑制分子PD-L1的表达。因此，抑制PTPRT是一种有前景的策略来增强抗肿瘤免疫。图2 研究示意图：肿瘤PTPRT缺失通过调节STING通路增强免疫检查点抑制剂疗效（Credit: Science Translational Medicine）参考文献 1. Morad, G., Helmink, B. A., Sharma, P. & Wargo, J. A. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell 184, 5309–5337 (2021). 2. Ma, X., Zhang, Y., Wang, S., Wei, H. & Yu, J. Immune checkpoint inhibitor (ICI) combination therapy compared to monotherapy in advanced solid cancer: A systematic review. J Cancer 12, 1318–1333 (2021). 3. Stanford, S. M. & Bottini, N. Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders. Nat Rev Drug Discov 22, 273–294 (2023). 4. Baumgartner, C. K. et al. The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity. Nature 622, 850–862 (2023). 5. Samson, N. & Ablasser, A. The cGAS–STING pathway and cancer. Nat Cancer 3, 1452–1463 (2022). 6. Motedayen Aval, L., Pease, J. E., Sharma, R. & Pinato, D. J. Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy. Journal of Clinical Medicine 9, 3323 (2020). https://www.science.org/doi/10.1126/scitranslmed.adl3598 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

免疫疗法

2024-09-04

·Armstrong生物药资讯

实体瘤CAR-T明星：Arsenal Bio完成3.25亿美元C轮融资

▎Armstrong 2024年9月4日，Arsenal Biosciences宣布完成3.25亿美元C轮融资，新投资机构包括ARCH Venture Partners、Milky Way Investments Group、再生元、英伟达风投基金、Luma Group，老投资人软银愿景基金二期、BMS、Westlake Village BioPartners、PICI、Kleiner Perkins、Byers Capial、Hitachi Ventures追加投资。 Arsenal Biosciences聚焦研发实体瘤CAR-T疗法，首发管线AB-1015用于治疗卵巢癌，已经进入临床阶段。 Arsenal Bio成立于2019年，当年完成8500万美元A轮融资，2022年完成2.2亿美元B轮融资，此次完成3.25亿美元C轮融资，累计融资金额达到6.3亿美元。Arsenal Bio的联合创始人Ken Drazan曾是一名肝移植外科医生，后从事风险投资。另一位联合创始人W.Nicholas Haining曾是默克研究实验室的发现肿瘤学和免疫学副总裁。 Arsenal Bio尝试通过多种技术手段来让CAR-T攻克实体瘤。 Arsenal采用CITE技术实现单点定点插入，而不是随机多点插入。 Arsenal Bio采用多个模块来改造CAR-T，包括精准插入、逻辑门、克服肿瘤微环境免疫抑制性等。 Logic gate的目的是让CAR-T在健康细胞中不会被激活，只有结合肿瘤细胞才会激活，具体而言是两个癌细胞同时表达的靶蛋白结合后才会激活。以首发管线AB-1015为例，靶向MSLN治疗卵巢癌，同时ALPG靶向用来实现肿瘤细胞特异性的激活，FAS shRNA用来规避TME的抑制性，PTPN2 shRNA用来优化CAR-T的杀伤效应。总结 CAR-T在血液瘤取得了很多突破，但实体瘤一直进展不大。Arsenal Biosciences针对这一问题，围绕CAR-T进行了系统化的工程化改造设计，与传统CAR-T有着非常大的不同。这些尝试也得到了众多基金包括MNC的认可，BMS、再生元等纷纷选择投资或合作。 Armstrong技术全梳理系列 GPRC5D靶点全梳理； CD40靶点全梳理； CD47靶点全梳理；补体靶向药物技术全梳理；补体药物：眼科治疗的重要方向； Claudin 6靶点全梳理； Claudin 18.2靶点全梳理；靶点冷暖，行业自知；中国大分子新药研发格局；被炮轰的“me too”；佐剂百年史；胰岛素百年传奇； CUSBEA：风雨四十载；中国新药研发的焦虑；中国生物医药企业的研发竞争；中国双抗竞争格局；中国ADC竞争格局；中国双抗技术全梳理；中国ADC技术全梳理； Ambrx技术全梳理； Vir Biotech技术全梳理； Immune-Onc技术全梳理；亘喜生物技术全梳理；康哲药业技术全梳理；科济药业技术全梳理；恺佧生物技术全梳理；同宜医药技术全梳理；百奥赛图技术全梳理；腾盛博药技术全梳理；创胜集团技术全梳理；永泰生物技术全梳理；中国抗体技术全梳理；德琪医药技术全梳理；德琪医药技术全梳理2.0；和铂医药技术全梳理；荣昌生物技术全梳理；再鼎医药技术全梳理；药明生物技术全梳理；恒瑞医药技术全梳理；豪森药业技术全梳理；正大天晴技术全梳理；吉凯基因技术全梳理；基石药业技术全梳理；百济神州技术全梳理；百济神州技术全梳理第2版；信达生物技术全梳理；信达生物技术全梳理第2版；中山康方技术全梳理；复宏汉霖技术全梳理；先声药业技术全梳理；君实生物技术全梳理；嘉和生物技术全梳理；志道生物技术全梳理；道尔生物技术全梳理；尚健生物技术全梳理；康宁杰瑞技术全梳理；科望医药技术全梳理；科望医药技术全梳理2.0；岸迈生物技术全梳理；礼进生物技术全梳理；康桥资本技术全梳理；余国良的抗体药布局；荃信生物技术全梳理；安源医药技术全梳理；三生国健技术全梳理；仁会生物技术全梳理；乐普生物技术全梳理；同润生物技术全梳理；宜明昂科技术全梳理；派格生物技术全梳理；迈威生物技术全梳理； Momenta技术全梳理； NGM技术全梳理；普米斯生物技术全梳理；普米斯生物技术全梳理2.0；三叶草生物技术全梳理；贝达药业抗体药全梳理；泽璟制药抗体药全梳理；恒瑞医药抗体药全梳理；齐鲁制药抗体药全梳理；石药集团抗体药全梳理；豪森药业抗体药全梳理；华海药业抗体药全梳理；科伦药业抗体药全梳理；百奥泰技术全梳理；凡恩世技术全梳理。

细胞疗法免疫疗法抗体药物偶联物