更新于：2024-05-01

NKG2A

killer cell lectin like receptor C1

更新于：2024-05-01

基本信息

别名

CD159 antigen-like family member A、CD159a、killer cell lectin like receptor C1

+ [10]

简介

(Microbial infection) Viruses like human cytomegalovirus have evolved an escape mechanism whereby virus-induced down-regulation of host MHC class I molecules is coupled to the binding of viral peptides to HLA-E, restoring HLA-E expression and inducing HLA-E-dependent NK cell immune tolerance to infected cells. Recognizes HLA-E in complex with human cytomegalovirus UL40-derived peptide (VMAPRTLIL) and inhibits NK cell cytotoxicity. Immune inhibitory receptor involved in self-nonself discrimination. In complex with KLRD1 on cytotoxic and regulatory lymphocyte subsets, recognizes non-classical major histocompatibility (MHC) class Ib molecule HLA-E loaded with self-peptides derived from the signal sequence of classical MHC class Ia molecules. Enables cytotoxic cells to monitor the expression of MHC class I molecules in healthy cells and to tolerate self (PubMed:9486650, PubMed:18083576, PubMed:9430220). Upon HLA-E-peptide binding, transmits intracellular signals through two immunoreceptor tyrosine-based inhibition motifs (ITIMs) by recruiting INPP5D/SHP-1 and INPPL1/SHP-2 tyrosine phosphatases to ITIMs, and ultimately opposing signals transmitted by activating receptors through dephosphorylation of proximal signaling molecules (PubMed:9485206, PubMed:12165520). Key inhibitory receptor on natural killer (NK) cells that regulates their activation and effector functions (PubMed:9486650, PubMed:9430220, PubMed:9485206, PubMed:30860984). Dominantly counteracts T cell receptor signaling on a subset of memory/effector CD8-positive T cells as part of an antigen-driven response to avoid autoimmunity (PubMed:12387742). On intraepithelial CD8-positive gamma-delta regulatory T cells triggers TGFB1 secretion, which in turn limits the cytotoxic programming of intraepithelial CD8-positive alpha-beta T cells, distinguishing harmless from pathogenic antigens (PubMed:18064301). In HLA-E-rich tumor microenvironment, acts as an immune inhibitory checkpoint and may contribute to progressive loss of effector functions of NK cells and tumor-specific T cells, a state known as cell exhaustion (PubMed:30503213, PubMed:30860984). (Microbial infection) May recognize HLA-E in complex with HIV-1 gag/Capsid protein p24-derived peptide (AISPRTLNA) on infected cells and may inhibit NK cell cytotoxicity, a mechanism that allows HIV-1 to escape immune recognition. (Microbial infection) Upon SARS-CoV-2 infection, may contribute to functional exhaustion of cytotoxic NK cells and CD8-positive T cells (PubMed:32203188, PubMed:32859121). On NK cells, may recognize HLA-E in complex with SARS-CoV-2 S/Spike protein S1-derived peptide (LQPRTFLL) expressed on the surface of lung epithelial cells, inducing NK cell exhaustion and dampening antiviral immune surveillance (PubMed:32859121).

关联

项与 NKG2A 相关的药物

Monalizumab

靶点

NKG2A

作用机制

NKG2A拮抗剂

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

BMS-986315

靶点

NKG2A

作用机制

NKG2A拮抗剂

在研机构

Bristol Myers Squibb Co.

原研机构

Bristol Myers Squibb Co.

在研适应症

非小细胞肺癌 [+1]

非在研适应症

神经痛

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

S-095029

靶点

NKG2A

作用机制

NKG2A拮抗剂 [+1]

在研机构

ADIR [+2]

原研机构

ADIR

在研适应症

非小细胞肺癌 [+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

项与 NKG2A 相关的临床试验

NCT06162572 / Not yet recruiting临床1/2期

A Phase 1b/2, Multicenter, Open-label Platform Study of Select Immunotherapy Combinations in Adult Participants With Previously Untreated Advanced Non-small Cell Lung Cancer (NSCLC) With High PD-L1 Expression

This is a Phase 1b/2 study evaluating the anti-PD1 antibody, cemiplimab, in combination with either S095018 (anti-TIM3 antibody), S095024 (anti-CD73 antibody), or S095029 (anti-NKG2A antibody) in adult participants with previously untreated advanced/metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression. The study includes two parts: part A, the combination-therapy safety lead-in phase to determine the recommended dose for expansion (RDE) for S095018, S095024, and S095029 in combination with cemiplimab and part B, the randomized dose expansion phase to assess the efficacy of S095018, S095024, or S095029 in combination with cemiplimab. Study treatment will be administered for a maximum of 108 weeks, or until confirmed disease progression per iRECIST and/ or until meeting other treatment discontinuation criteria.

开始日期2024-04-30

申办/合作机构

Servier Bio-Innovation LLC

[+2]

NCT06116136 / Not yet recruiting临床1/2期

Open Label, Non-randomized, Phase 1b/2 Trial Investigating the Safety, Tolerability, and Antitumor Activity of S095029 (Anti-NKG2A Antibody) as a Part of Combination Therapy in Participants With Locally Advanced and Unresectable or Metastatic MSI-H/dMMR Gastro-esophageal Junction /Gastric Cancer

This study will investigate the safety, tolerability, and antitumor activity of S095029 (anti-NKG2A antibody) in combination with pembrolizumab in in microsatellite instability-high/Defective mismatch repair (MSI-H/dMMR) locally advanced unresectable or metastatic gastric /GEJ adenocarcinomas.

开始日期2024-04-15

申办/合作机构

Servier Bio-Innovation LLC

[+2]

NCT06289894 / Not yet recruiting临床1期

A Phase I, Open-label, Single Arm Study to Evaluate the Safety, Tolerability, and Antitumor Activity of BRY805 in Participants With Advanced Solid Tumors

This is a phase 1 open label multicenter study to evaluate safety, tolerance and the maximum tolerance of BRY805 administered intravenously (IV) once every three weeks in participants with advanced solid tumors, so as to confirm the recommended phase 2 dose of BRY805 and obtain the preliminary efficacy information of participants with advanced solid tumors.

开始日期2024-03-01

申办/合作机构

浙江博锐生物制药有限公司

100 项与 NKG2A 相关的临床结果

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100 项与 NKG2A 相关的转化医学

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0 项与 NKG2A 相关的专利（医药）

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1,355

项与 NKG2A 相关的文献（医药）

2024-02-15·NPJ Parkinson's disease

Distinctive CD56^dim NK subset profiles and increased NKG2D expression in blood NK cells of Parkinson's disease patients.

Article

作者: Stephen Weber ; Kelly B Menees ; Jieun Park ; Julian Agin-Liebes ; Chih-Chun Lin ; Roy N Alcalay ; Jae-Kyung Lee

Mounting data suggest an important role for the immune system in Parkinson's disease (PD). Previous evidence of increased natural killer (NK) cell populations in PD suggests a potential role of NK cells in the pathogenesis of the disease. Previous studies have analyzed NK cell populations using aggregation by variable expression of CD56 and CD16. It remains unknown what differences may exist between NK cell subpopulations when stratified using more nuanced classification. Here, we profile NK cell subpopulations and elucidate the expressions of activating, NKG2D, inhibitory, NKG2A, and homing, CX3CR1, receptors on NK cell subpopulations in PD and healthy controls (HC). We analyzed cryopreserved PMBC samples using a 10-color flow cytometry panel to evaluate NK cell subpopulations in 31 individuals with sporadic PD and 27 HC participants. Here we identified significant differences in the CD56^dim NK subset that changes with disease severity in PD. Furthermore, the expressions of NKG2D in all three NK cell subsets were significantly elevated in PD patients compared to HC. Notably, NKG2A expression in the CD56^bright NK subset increased in PD patients with longer disease duration but there were no changes in CX3CR1. In summary, our data suggests that changes in NK cells may be influenced by the clinical severity and duration of PD.

2024-02-05·International immunopharmacology

Enhanced NK cell activation via eEF2K-mediated potentiation of the cGAS-STING pathway in hepatocellular carcinoma.

Article

作者: Yan Xu ; Fang Sun ; Yuying Tian ; Guineng Zeng ; Guanglin Lei ; Zhifang Bai ; Yonggang Wang ; Xinlan Ge ; Jing Wang ; Chaohui Xiao ; Zhaohai Wang ; Minggen Hu ; Jianxun Song ; Penghui Yang ; Rong Liu

BACKGROUND:

Liver cancer, particularly hepatocellular carcinoma (HCC), is characterized by a high mortality rate, attributed primarily to the establishment of an immunosuppressive microenvironment. Within this context, we aimed to elucidate the pivotal role of eukaryotic elongation factor 2 kinase (eEF2K) in orchestrating the infiltration and activation of natural killer (NK) cells within the HCC tumor microenvironment. By shedding light on the immunomodulatory mechanisms at play, our findings should clarify HCC pathogenesis and help identify potential therapeutic intervention venues.

METHODS:

We performed a comprehensive bioinformatics analysis to determine the functions of eEF2K in the context of HCC. We initially used paired tumor and adjacent normal tissue samples from patients with HCC to measure eEF2K expression and its correlation with prognosis. Subsequently, we enrolled a cohort of patients with HCC undergoing immunotherapy to examine the ability of eEF2K to predict treatment efficacy. To delve deeper into the mechanistic aspects, we established an eEF2K-knockout cell line using CRISPR/Cas9 gene editing. This step was crucial for verifying activation of the cGAS-STING pathway and the subsequent secretion of cytokines. To further elucidate the role of eEF2K in NK cell function, we applied siRNA-based techniques to effectively suppress eEF2K expression in vitro. For in vivo validation, we developed a tumor-bearing mouse model that enabled us to compare the infiltration and activation of NK cells within the tumor microenvironment following various treatment strategies.

RESULTS:

We detected elevated eEF2K expression within HCC tissues, and this was correlated with an unfavorable prognosis (30.84 vs. 20.99 months, P = 0.033). In addition, co-culturing eEF2K-knockout HepG2 cells with dendritic cells led to activation of the cGAS-STING pathway and a subsequent increase in the secretion of IL-2 and CXCL9. Moreover, inhibiting eEF2K resulted in notable NK cell proliferation along with apoptosis reduction. Remarkably, after combining NH125 and PD-1 treatments, we found a significant increase in NK cell infiltration within HCC tumors in our murine model. Our flow cytometry analysis revealed reduced NKG2A expression and elevated NKG2D expression and secretion of granzyme B, TNF-α, and IFN-γ in NK cells. Immunohistochemical examination confirmed no evidence of damage to vital organs in the mice treated with the combination therapy. Additionally, we noted higher levels of glutathione peroxidase and lipid peroxidation in the peripheral blood serum of the treated mice.

CONCLUSION:

Targeted eEF2K blockade may result in cGAS-STING pathway activation, leading to enhanced infiltration and activity of NK cells within HCC tumors. The synergistic effect achieved by combining an eEF2K inhibitor with PD-1 antibody therapy represents a novel and promising approach for the treatment of HCC.

2024-02-02·Journal for immunotherapy of cancer

Phase 1/2 study of monalizumab plus durvalumab in patients with advanced solid tumors.

Article

作者: Sandip P Patel ; Teresa Alonso-Gordoa ; Susana Banerjee ; Ding Wang ; Jarushka Naidoo ; Nathan E Standifer ; Doug C Palmer ; Lin-Yang Cheng ; Panagiotis Kourtesis ; Maria L Ascierto ; Mayukh Das ; Jennifer R Diamond ; Matthew D Hellmann ; Benedito A Carneiro

BACKGROUND:

The combination of monalizumab (anti-NKG2A/CD94) and durvalumab (anti-programmed death ligand-1) may promote antitumor immunity by targeting innate and adaptive immunity. This phase 1/2 study of monalizumab and durvalumab evaluated safety, antitumor activity, and pharmacodynamics in patients with advanced solid tumors.

MAIN BODY:

Immunotherapy-naïve patients aged ≥18 years with advanced disease, Eastern Cooperative Oncology Group performance status of 0-1, and 1-3 prior lines of systemic therapy in the recurrent/metastatic setting were enrolled. In part 1 (dose escalation), patients received durvalumab 1500 mg every 4 weeks (Q4W) with increasing doses of monalizumab Q2W/Q4W (n=15). Dose expansion in part 1 included patients with cervical cancer (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W) or metastatic microsatellite stable (MSS)-colorectal cancer (CRC) (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q4W). In part 2 (dose expansion), patients with MSS-CRC (n=40), non-small cell lung cancer (NSCLC; n=20), MSS-endometrial cancer (n=40), or ovarian cancer (n=40) received durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W. The primary endpoint was safety. Secondary endpoints included antitumor activity per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Exploratory analyses included assessment of T-cell and natural killer (NK) cell activation and proliferation in peripheral blood and the tumor microenvironment (TME). The study enrolled 185 patients (part 1, 45; part 2, 140). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. In part 2, the most common treatment-related adverse events were fatigue (12.1%), asthenia (9.3%), diarrhea (9.3%), pruritus (7.9%), and pyrexia (7.1%). In the expansion cohorts, response rates were 0% (cervical), 7.7% (MSS-CRC), 10% (NSCLC), 5.4% (ovarian), and 0% (MSS-endometrial). Sustained NK cell activation, CD8⁺ T-cell proliferation, increased serum levels of CXCL10 (C-X-C motif chemokine ligand 10) and CXCL11, and increased tumor infiltration of CD8⁺ and granzyme B⁺ cells were observed.

CONCLUSIONS:

Although efficacy was modest, monalizumab plus durvalumab was well tolerated and encouraging immune activation was observed in the peripheral blood and TME.

TRIAL REGISTRATION NUMBER:

NCT02671435.

项与 NKG2A 相关的新闻（医药）

2024-03-04

·Business Wire

Common Immune Response Protective Across Many Diseases

SEATTLE--( BUSINESS WIRE )--Combined, infection, autoimmunity and cancer account for four out of every 10 deaths worldwide, and represent major global health challenges. In a just-published paper in the journal Cell Reports , Institute for Systems Biology (ISB) researchers highlight a novel discovery of how the human immune system works in common ways across diseases, and offer promising avenues for exploring multi-disease therapeutic strategies. Many therapies, while effective for one class of disease, may aggravate others. Cancer treatments like immune checkpoint blockade, for example, can trigger autoimmunity. Similarly, drugs targeting autoimmune diseases may leave patients more susceptible to infections and cancer. “Understanding shared human immune system characteristics across these disease contexts is crucial for identifying potential therapeutic strategies that could treat a patient’s primary ailment while not triggering secondary conditions,” said ISB President Dr. Jim Heath, corresponding author of the paper. To address these challenges, ISB researchers have identified two immune cell receptors – NKG2A and NKG2C – as factors influencing immune responses across diseases. These receptors, which are not seen together on the same cells, have gained significant interest in the immunology community for their ability to regulate the function of T cells and natural killer cells. The research team examined deep clinical and biological data of 526 patients with infection, 162 patients with lupus, and 11,180 patients with cancer, considering whether the patients’ T cells or natural killer immune cells could be classified as NKG2A biased or NKG2C biased. Through a comprehensive analysis, they found that an NKG2A-dominant immune response correlates with decreased disease severity and mortality, and lower prevalence of post-acute chronic conditions across all disease contexts. “Patients with more NKG2A activity showed decreased inflammation and increased survival rates across different disease contexts, including viral infections, autoimmune diseases like lupus, and various cancer types,” said Daniel Chen, first author of the paper. The study also identified distinct immune cell profiles associated with NKG2A and NKG2C biases, which could lead to potential therapeutic targets for modifying immune responses across diseases. It also suggests that treating NKG2A as a drug target for cancer immunotherapy, which is an idea that has been pursued in oncology clinical trials, would likely not be successful. The study’s findings are, in fact, consistent with what has been found in those trials. “We plan future studies to delve deeper into the biological mechanisms underlying these immune biases, which we believe will lead to developing more targeted and effective treatments,” Heath said. About ISB Institute for Systems Biology (ISB) is a collaborative and cross-disciplinary non-profit biomedical research organization based in Seattle. We focus on some of the most pressing issues in human health, including aging, brain health, cancer, COVID-19, as well as many infectious diseases. Our science is translational, and we champion sound scientific research that results in real-world clinical impacts. ISB is an affiliate of Providence, one of the largest not-for-profit health care systems in the United States. Follow us online at isbscience.org , and on YouTube , Facebook , LinkedIn , X (formerly Twitter) and Instagram .

免疫疗法

2024-02-15

·医药观澜

300多款抗肿瘤1类新药获批临床，小分子新药占比近40%！（附PDF）

▎药明康德内容团队编辑癌症是威胁人类健康的主要疾病之一，也是创新药研发领域的主要方向。根据IQVIA 2023全球研发趋势报告，在全球在研疗法中，抗肿瘤疗法占比在2022年已达到38%，在过去5年的复合年均增长率（CAGR）为10.5%。在中国，近年来也有越来越多的抗肿瘤新药开始进入临床阶段。根据中国国家药监局药品审评中心（CDE）官网“临床试验默示许可”专栏，2023年首次在中国获批临床试验的1类新药中，有300多款为抗肿瘤1类新药，占比超过50%。本文中就让我们看看这些在研的抗肿瘤1类新药都有哪些？它们都有望解决目前肿瘤治疗领域的哪些难题？（扫描下方二维码，可获取2023年首次在中国获批临床的抗肿瘤1类新药PDF文件）实体瘤疗法占比超50% 从获批临床的适应症来看，2023年首次获批临床的抗肿瘤1类新药拟开发的适应症涵盖了多种实体瘤和血液系统恶性肿瘤。其中，针对“实体瘤”适应症开发的新药占比超50%。其适应症涵盖了HER2表达的实体瘤、CD73表达实体瘤、MAPK信号通路异常的晚期实体肿瘤、CLDN18.2阳性实体瘤、KRAS突变实体瘤、HPV18+实体瘤、GPC3阳性实体瘤、FAP阳性实体瘤、NTRK或ROS1基因融合的实体瘤、表达B7-H6的实体瘤等等。除此之外，还有其他新药拟开发治疗非小细胞肺癌、乳腺癌、卵巢癌、胃癌、前列腺癌、脑胶质瘤等实体瘤适应症。此外，还有几十款新药针对适应症为各种类型的血液系统肿瘤，包括非霍奇金淋巴瘤、多发性骨髓瘤、B细胞恶性肿瘤、急性髓系白血病、骨髓增生异常综合征等。小分子新药占比近40%，多种分子类型百花齐放从药物类型来看，2023年首次在中国获批临床的抗肿瘤1类新药涵盖了小分子药物、抗体药物、抗体偶联药物（ADC）、细胞疗法、核酸药物、放射性药物、活菌药物、溶瘤病毒药物等多种分子类型。 2023年首次在中国获批临床的抗肿瘤1类新药-分子类型分布小分子药物的许多优势使得其在治疗上有着无可取代的地位，且仍然是当下新药开发的主要类型。我们统计的300多款抗肿瘤1类新药中包含了120余款小分子新药，占比接近40%。这些新药涵盖了许多靶点，如EZH2、SHP2、FGFR、BCL-2、PI3Kδ、CDK7、CDK9、CDK4、PD-1/PD-L1、BTK、TLR8、KRAS、HIF-2α等等。值得一提的是，多家公司有2款及以上的小分子抗肿瘤1类新药获批临床，包括：贝达药业的转录增强因子TEAD小分子抑制剂、HIF-2α抑制剂、CD73核苷酶抑制剂；百济神州的新一代BCL-2抑制剂、HPK1抑制剂；和誉医药的FGFR抑制剂、新一代EGFR Exon20ins抑制剂、CD73抑制剂；恒瑞医药的调控多种癌基因表达的小分子新药、AR抑制剂、CDK4抑制剂；加科思的GUE抑制剂、PARP7抑制剂；辉瑞（Pfizer）的SHP2抑制剂、EZH2抑制剂、KAT6A表观遗传修饰剂；石药集团的ATM抑制剂、SOS1抑制剂；同源康医药的CDK7抑制剂、小分子EGFR/HER2抑制剂、CDK2/4/6抑制剂；泽璟制药的TLR8激动剂、泛KRAS突变抑制剂等等。在小分子药物中，蛋白降解疗法因可以靶向以前被认为“不可成药”的靶点，而成为近年来备受关注的新药开发类型。2023年，十多款蛋白降解疗法也在中国进入临床研究阶段，包括靶向蛋白降解嵌合体、分子胶药物等。这些药物来自海思科、贝达药业、福沃药业、珃诺生物、国匡医药、分迪药业、标新生物、格博生物、齐鲁制药、海创药业等等，拟开发用于治疗不同类型的实体瘤和血液肿瘤。数据来源：CDE、各公司新闻稿。本表为不完全统计，如有遗漏，欢迎补充除了小分子药物，2023年首次获批临床的抗肿瘤1类新药中还有超80款抗体疗法，包括单抗、双抗、三抗等。其中，单抗类产品的靶点涵盖了CD38、CD73、CD70、CD47、TNFR2、NKG2A、OX40、Claudin18.2、LIF、PVRIG、B7H7、Siglec-15、TIM-3等等；双抗类产品的靶点涵盖PD-1/CTLA-4、PD-L1/CD40、PD-1/CD73、SIRPα/PD-L1、CD3/ROR1、MUC16/CD3、LAG-3/TIGIT、CEA/CD3、EpCAM/CD3、STEAP1/CD3、HER2/CD47、GPRC5D/CD3等等。此外，来自赛诺菲（Sanofi）、贝达药业、惠和生物、拓创生物、道尔生物、天广实、泽璟制药等公司的约10款三特异性抗体产品获批临床，包括了HER2/CD3/CD28三特异性T细胞接合剂、靶向CD123/NKp46/CD16的三抗、CD3/GPRC5D/BCMA三抗等等。在抗体偶联药物（ADC）方面，2023年有约40款ADC产品首次在中国获批临床，这些产品的靶点涵盖了Claudin18.2、FRα、Nectin-4、HER2、HER3、CDH3、Trop-2、CD33、CD70、EGFR-cMET、FAP、PD-L1、AXL、DLL3等。值得一提的是，多家公司在中国有2款及以上的ADC产品获批临床，包括：复宏汉霖靶向EGFR的ADC、靶向PD-L1的ADC；普方生物靶向FRα的ADC、靶向CD70的ADC；映恩生物靶向HER3的ADC以及另一款基于拓扑异构酶-1抑制剂的ADC；阿斯利康（AstraZeneca）靶向EGFR-cMET的ADC、靶向FRα的ADC等等。细胞疗法方面，2023年有约40款细胞治疗药物在中国获得临床试验默示许可，其中包含了CAR-T细胞疗法、CAR-NK细胞疗法、TCR-T细胞疗法、TIL疗法、恒定自然杀伤T细胞（iNKT）疗法、DC疫苗产品等等。其中，CAR-T疗法的数量占比最多，有近20款。这些产品来自亘喜生物、凯地医疗、康佰裕生物、合源生物、森朗生物、信达生物、恒润达生、原启生物、精准生物、科棋药业等，靶点涵盖了BCMA和CD19双靶点、CD22和CD19双靶点、NKG2DL、MSLN、GPRC5D、CD70、CD7、GPC3等。数据来源：CDE、各公司新闻稿。本表为不完全统计，如有遗漏，欢迎补充放射性药物可以利用同一配体分别开发针对特定靶点的诊断和治疗产品，具有独特的“诊疗一体化”优势，因此近年来备受行业看好。2023年也有接近10款放射性1类新药在中国获批临床，分别来自Telix公司、远大医药、恒瑞医药、晶核生物、蓝纳成生物等，其靶点涵盖SSTR、PSMA、FAP，正在被开发用于治疗胶质母细胞瘤、神经内分泌肿瘤、PSMA阳性前列腺癌、FAP阳性晚期实体瘤等等。除了上述产品，2023年首次获批临床的抗肿瘤1类新药中还包含了许多其他分子类型，例如mRNA药物、DNA核酸药物、活菌药物、溶瘤病毒/重组腺病毒药物等等。限于篇幅，本文不再一一介绍。希望这些新药后续临床研究顺利进行，早日造福患者！如果您想了解更多信息，请扫描下方二维码，您将获得药明康德内容团队整理的《2023年首次在中国获批临床的抗肿瘤1类新药》完整PDF文件。参考资料：[1]中国国家药监局药品审评中心（CDE）官网.From https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c[2]各公司官方网站及新闻稿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「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。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。

抗体药物偶联物申请上市临床申请临床1期放射疗法

2024-02-03

·今日头条

免疫逃避“元凶”！复旦大学徐洁杰、郭剑明发文：助力“克服”癌症免疫治疗耐药性

本文为转化医学网原创，转载请注明出处作者：Sophia 导读：免疫疗法正在获得发展势头，但目前的治疗方法在受益者方面存在局限性。透明细胞肾细胞癌（ccRCC）在所有实体瘤中含有最高表达的人白细胞抗原 E （HLA-E），即 NKG2A 的配体。在这项研究中，我们旨在研究NKG2ACD8 T细胞在肿瘤微环境中的作用及其作为ccRCC新靶点的潜力。近日，复旦大学基础医学院徐洁杰教授联合复旦大学附属中山医院郭剑明教授共同通讯在期刊《Journal for Immuno Therapy of Cancer》上发表文章“NKG2ACD8 T cells infiltration determines immunosuppressive contexture and inferior response to immunotherapy in clear cell renal cell carcinoma”，研究发现ccRCC 中 NKG2ACD8 T 细胞浸润较高的患者表现出较短的总生存期和对免疫治疗的耐药性。NKG2ACD8 T 细胞表达上调的检查点分子，并显示出受损的效应功能，以及组织驻留特征。程序性细胞死亡蛋白-1 （PD-1）阻断和 NKG2A 阻断的组合证明了重新激活 CD8 T 细胞效应器功能的增强能力。 https://jitc.bmj.com/content/12/1/e008368 研究背景 01 肾细胞癌（RCC）是泌尿系统三大恶性肿瘤之一。2020年，全球新发肾细胞癌病例超过40万例，其中透明细胞肾细胞癌（ccRCC）约占75%，是最常见的病理类型。与非转移性局限性 ccRCC 患者的 5 年生存概率较高（超过 80%）相比，其他 20%-50% 的转移性肾细胞癌（mRCC）患者的生存率会大大降低，大多数仅在手术后 3 年内发生。在过去十年中，免疫疗法彻底改变了mRCC的治疗。与单独使用酪氨酸激酶抑制剂（TKI）相比，III期试验的最新结果表明，基于免疫检查点阻断（ICB）加TKI的联合治疗显着改善了mRCC患者的预后。因此，亟需探索mRCC患者新的治疗方法。有趣的是，与其他肿瘤不同，CD8 T 细胞的强烈浸润与 ccRCC 的较差预后相关，这可能是由于不同 CD8 T 细胞亚型的功能细分。我们小组之前还发现，在ccRCC中，TNFRSF9CD8 T细胞同时具有耗竭和效应表型，CXCL13CD8 T细胞具有抗肿瘤功能受损的耗竭表型。 NKG2A 是 C 型凝集素家族成员，可在细胞表面与 CD94 形成二聚体。与程序性细胞死亡蛋白-1/程序性细胞死亡配体 1 （PD-1/PD-L1）通路不同，NKG2A 独立于 T 细胞受体（TCR）起作用。非经典的主要组织相容性复合物-I 分子人白细胞抗原-E （HLA-E）是 NKG2A-CD94 的主要配体。在实体瘤中，ccRCC代表了HLA-E表达的最高水平。据报道，NKG2A 主要在 CD8αβ T 细胞、CD56hi 自然杀伤（NK）细胞和自然杀伤 T （NKT）细胞中表达。NKG2A-CD94与HLA-E结合可抑制T细胞和NK细胞的活化。先前的研究表明，NKG2A拮抗作用主要通过NKG2ACD8 T细胞而不是NKG2A NK细胞在肿瘤疫苗治疗耐药个体中发挥作用。然而， NKG2ACD8 T细胞在肿瘤微环境（TME）中的作用以及靶向NKG2A在ccRCC中的治疗效果仍然未知。研究进展 02 由于 NKG2A CD8 T 细胞的较高浸润与对免疫治疗的反应较差有关，因此我们通过使用新鲜 ccRCC 组织的体外干预模型进一步探索了这些患者的潜在治疗方法。干预分为4组，即对照组、PD-1单克隆抗体（nivolumab）治疗组、NKG2A单克隆抗体（mAb）治疗组和联合治疗组（图 5A）。在纳武利尤单抗体外干预后，CD8 T细胞上NKG2A表达较低的患者在CD8 T细胞中表现出IFN-γ和GZMB的显著上调（图5B-D），证实了NKG2A CD8 T细胞浸润较高的患者对免疫治疗的反应较差。此外，在纳武利尤单抗干预后，CD8 T细胞显示NKG2A的表达增加（图5E;p=0.047），这表明基于抗NKG2A和抗PD-1的联合治疗可能增加PD-1阻断单药治疗的潜在价值。 NKG2A 阻断与抗 PD-1 疗法协同作用，重振 CD8 T 细胞的细胞毒性随后，我们对不同干预方案下CD8 T细胞内的动态功能改变进行了全面评估。值得注意的是，接受抗NKG2A治疗以及NKG2A和PD-1联合抑制组均表现出CD8 T细胞脱颗粒功能（CD107a）的显著增强（图5F;p=0.047和p=0.013），而接受纳武利尤单抗治疗的组未能表现出这种改善（图5F;p=0.241）。抗NKG2A和抗PD-1治疗的组合增强了CD8 T细胞的细胞毒性，仅在组合治疗组中观察到IFN-γ分泌显著增加（图5G;p=0.017），并且优于抗NKG2A单药治疗组（图5G;p=0.011）。此外，值得注意的是，组合疗法可以显著提高CD8 T细胞内GZMB的表达（图5H;p = 0.007）。但TCF-7的表达没有差异（图 5I）。总体而言，这些发现表明，抗 PD-1 和抗 NKG2A 的联合治疗可增强 CD8 T 细胞效应功能，这可能使抗 PD-1/PD-L1 免疫治疗耐药的患者受益。研究结论 03 本研究表明，在ccRCC中，NKG2ACD8 T细胞与不良预后和对免疫治疗的反应有关。NKG2ACD8 T 细胞表现出耗竭的表型，并且与炎症但免疫抑制的微环境有关，并伴有富集的调节性 CD4 T 细胞（Tregs）浸润。NKG2A 阻断和当前免疫疗法的协同相互作用表现出重新激活 ccRCC 中 CD8 T 细胞效应功能的强大能力。总之，抗程序性细胞死亡蛋白-1（PD-1）和抗NKG2A的联合治疗可增强CD8 T细胞效应功能，这可能成为克服ccRCC当前免疫治疗耐药性的有效方法。参考资料： https://jitc.bmj.com/content/12/1/e008368 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜3月01日-02日 ▶第三届长三角单细胞组学技术应用论坛暨空间组学前沿论坛将在上海召开，诚邀您的参与！点击对应文字查看详情

免疫疗法临床3期