作者: Schmitz, Marc ; Lahoud, Mireille H ; Miles, John J ; Pearson, Frances E ; Bridgeman, John S ; Leal‐Rojas, Ingrid M ; Haigh, Oscar L ; Walpole, Carina ; Llewellyn‐Lacey, Sian ; Price, David A ; McLaren, James E ; Tullett, Kirsteen M ; Masterman, Kelly‐Anne ; Radford, Kristen J ; Ladell, Kristin ; Miners, Kelly ; Tunger, Antje

AbstractObjectivesVaccines that prime Wilms' tumor 1 (WT1)‐specific CD8+ T cells are attractive cancer immunotherapies. However, immunogenicity and clinical response rates may be enhanced by delivering WT1 to CD141+ dendritic cells (DCs). The C‐type lectin‐like receptor CLEC9A is expressed exclusively by CD141+ DCs and regulates CD8+ T‐cell responses. We developed a new vaccine comprising a human anti‐CLEC9A antibody fused to WT1 and investigated its capacity to target human CD141+ DCs and activate naïve and memory WT1‐specific CD8+ T cells.MethodsWT1 was genetically fused to antibodies specific for human CLEC9A, DEC‐205 or β‐galactosidase (untargeted control). Activation of WT1‐specific CD8+ T‐cell lines following cross‐presentation by CD141+ DCs was quantified by IFNγ ELISPOT. Humanised mice reconstituted with human immune cell subsets, including a repertoire of naïve WT1‐specific CD8+ T cells, were used to investigate naïve WT1‐specific CD8+ T‐cell priming.ResultsThe CLEC9A‐WT1 vaccine promoted cross‐presentation of WT1 epitopes to CD8+ T cells and mediated priming of naïve CD8+ T cells more effectively than the DEC‐205‐WT1 and untargeted control‐WT1 vaccines.ConclusionsDelivery of WT1 to CD141+ DCs via CLEC9A stimulates CD8+ T cells more potently than either untargeted delivery or widespread delivery to all Ag‐presenting cells via DEC‐205, suggesting that cross‐presentation by CD141+ DCs is sufficient for effective CD8+ T‐cell priming in humans. The CLEC9A‐WT1 vaccine is a promising candidate immunotherapy for malignancies that express WT1.

2020-01-01·Clinical & Translational Immunology3区 · 医学

Enhancing chimeric antigen receptor T‐cell immunotherapy against cancer using a nanoemulsion‐based vaccine targeting cross‐presenting dendritic cells

3区 · 医学

ArticleOA

作者: Ali, Aesha I ; Dolcetti, Riccardo ; Slaney, Clare Y ; Oliver, Amanda J ; von Scheidt, Bianca ; Chan, Jack D ; Thomas, Ranjeny ; Davey, Ashleigh S ; Kershaw, Michael H ; Darcy, Phillip K ; Zeng, Bijun ; Trapani, Joseph A

AbstractObjectivesAdoptive transfer of chimeric antigen receptor (CAR)‐modified T cells is a form of cancer immunotherapy that has achieved remarkable efficacy in patients with some haematological cancers. However, challenges remain in CAR T‐cell treatment of solid tumours because of tumour‐mediated immunosuppression.MethodsWe have demonstrated that CAR T‐cell stimulation through T‐cell receptors (TCRs) in vivo can generate durable responses against solid tumours in a variety of murine models. Since Clec9A‐targeting tailored nanoemulsion (Clec9A‐TNE) vaccine enhances antitumour immune responses through selective activation of Clec9A+ cross‐presenting dendritic cells (DCs), we hypothesised that Clec9A‐TNE could prime DCs for antigen presentation to CAR T cells through TCRs and thus improve CAR T‐cell responses against solid tumours. To test this hypothesis, we used CAR T cells expressing transgenic TCRs specific for ovalbumin (OVA) peptides SIINFEKL (CAROTI) or OVA323‐339 (CAROTII).ResultsWe demonstrated that the Clec9A‐TNEs encapsulating full‐length recombinant OVA protein (OVA‐Clec9A‐TNE) improved CAROT T‐cell proliferation and inflammatory cytokine secretion in vitro. Combined treatment using the OVA‐Clec9A‐TNE and CAROT cells resulted in durable responses and some rejections of tumours in immunocompetent mice. Tumour regression was accompanied by enhanced CAROT cell proliferation and infiltration into the tumours.ConclusionOur study presents Clec9A‐TNE as a prospective avenue to enhance CAR T‐cell efficacy for solid cancers.

PLOS Pathogens1区 · 医学

IL-12p40/IL-10 Producing preCD8α/Clec9A+ Dendritic Cells Are Induced in Neonates upon Listeria monocytogenes Infection

1区 · 医学

ArticleOA

作者: Shortman, Ken ; Köhler, Arnaud ; Lahoud, Mireille H ; Torres, David ; Delbauve, Sandrine ; Flamand, Véronique ; Caminschi, Irina

Infection by Listeria monocytogenes (Lm) causes serious sepsis and meningitis leading to mortality in neonates. This work explored the ability of CD11c(high) lineage DCs to induce CD8+ T-cell immune protection against Lm in mice before 7 days of life, a period symbolized by the absence of murine IL-12p70-producing CD11c(high)CD8α+ dendritic cells (DCs). We characterized a dominant functional Batf3-dependent precursor of CD11c(high) DCs that is Clec9A+CD205+CD24+ but CD8α- at 3 days of life. After Lm-OVA infection, these pre-DCs that cross-present Ag display the unique ability to produce high levels of IL-12p40 (not IL-12p70 nor IL-23), which enhances OVA-specific CD8+ T cell response, and regulatory IL-10 that limits OVA-specific CD8+ T cell response. Targeting these neonatal pre-DCs for the first time with a single treatment of anti-Clec9A-OVA antibody in combination with a DC activating agent such as poly(I:C) increased the protection against later exposure to the Lm-OVA strain. Poly(I:C) was shown to induce IL-12p40 production, but not IL-10 by neonatal pre-DCs. In conclusion, we identified a new biologically active precursor of Clec9A+ CD8α- DCs, endowed with regulatory properties in early life that represents a valuable target to augment memory responses to vaccines.

项与 Anti-CLEC9A antibody(Monash University/University of Queensland) 相关的新闻（医药）

2024-01-23

·奇点网

T细胞与DC一相逢，新型癌症免疫疗法就诞生了！

*仅供医学专业人士阅读参考很多重要的发现都来自于意外。2021年，刘龙超等人在著名期刊《自然·生物医学工程》上发表了一篇研究论文[1]。他们原本打算设计一个同时靶向T细胞和肿瘤细胞的双特异性T细胞衔接器（BiTEs），一方面阻断PD-L1/PD-1通路；另一方面拉进T细胞与肿瘤细胞的距离，增强其杀伤效果。然而实验结果却出乎他们的预料，发挥抗肿瘤作用的竟然不是BiTEs同时作用于肿瘤细胞和T细胞，而是同时作用于树突状细胞（DCs）和T细胞。一旦阻止BiTEs与DCs的相互作用，BiTEs的抗肿瘤效果就消失了。从作用机制上看，这个BiTEs在拉近DC和T细胞的距离之后，可以通过抗原呈递和共刺激信号共同激活T细胞，增强T细胞的抗肿瘤能力。基于上述发现，刘龙超等人提出，靶向DC和T细胞的BiTEs或许才是恢复T细胞持久抗肿瘤免疫的通用方法。机制示意图时隔两年之后，由以色列魏茨曼科学研究所Ido Amit和Rony Dahan领衔的研究团队，在顶级期刊《细胞》杂志上发表一篇重磅研究成果，系统阐述了同时靶向DC和T细胞的双特异性抗体发挥抗肿瘤免疫作用的机制[2]。他们在分析近13万个T细胞的数据之后，发现对免疫治疗有反应的T细胞与DC存在相互作用，而拉近DC和T细胞距离，让二者亲密接触的双特异性抗体，可以促进T细胞的激活和增殖，增强T细胞的抗肿瘤活性。他们还在BiTEs的基础上，给靶向DC和T细胞的双特异性抗体取了个新名字——双特异性DC-T细胞衔接器（BiCEs），以示区别。以上两个研究的研究成果表明，一种崭新的癌症免疫疗法即将诞生。论文首页截图大量研究表明，作为抗原递呈细胞，DC尤其是经典的1型树突状细胞（cDC1s）在抗肿瘤免疫和免疫治疗中发挥着巨大的作用。因此，从理论上讲，增强cDC1s和T细胞在肿瘤中的相互作用，应该就可以增强抗肿瘤免疫。在研究开始之初，Amit团队先基于小鼠模型，探索了免疫检查点抑制剂对cDC1s和T细胞之间关系的影响。在分析近13万个T细胞的转录组数据之后，他们发现响应免疫治疗的T细胞高表达cDC1s招募基因模块。此外，他们还在cDC1s细胞耗竭或存在的情况下，检测了免疫检查点抑制剂的治疗效果。结果发现，只有在cDC1s存在的情况下，免疫检查点抑制剂才会导致肿瘤特异性CD8阳性T细胞水平增加，并发挥抗肿瘤作用。DC对免疫检查点抑制剂的疗效至关重要在上述结论的基础上，Amit团队想到，在肿瘤组织中，cDC1s与T细胞的相遇并结合并不简单，毕竟cDC1s细胞在肿瘤中相对罕见，仅占所有免疫细胞的比例约为1%左右。因此，他们假设，T细胞-cDC1相互作用的概率低，可能是T细胞介导的免疫检查点抑制剂疗效限制的关键因素。这个假设支持他们设计一种能拉近cDC1s和T细胞之间距离的双特异性抗体，也就是文章开头提到的双特异性DC-T细胞衔接器（BiCEs）。他们设计的这个BiCEs一边与T细胞表面的PD-1结合，另一边与cDC1表面标记物CLEC9A（DNGR1）结合。与刘龙超等人的研究类似，这个双抗不仅可以让cDC1s和T细胞接触，还可以阻断PD-L1/PD-1，发挥双重抗癌作用。BiCE的结构此外，他们还设计了一个只与T细胞表面PD-1结合的类似BiCE的双抗（PD-1/IC bsAb）作为对照使用。体外的初步研究数据显示，与抗CLEC9A单抗、抗PD-1单抗和PD-1/IC bsAb相比，BiCE确实能以剂量依赖的方式促进cDC1s与T细胞的结合。BiCE促进cDC1s与T细胞结合基于黑色素瘤小鼠模型的研究数据显示，在注射PD-1/CLEC9A BiCE的24小时后，就可以观察到引流淋巴结（dLN）中T细胞与cDC1双联的频率增加，而注射其他抗体则没有这种情况出现。与刘龙超等人的研究一致，Amit团队也发现，在肿瘤和引流淋巴结中与T细胞结合的cDC1主要是迁移性cDC1（CD103阳性），而不是驻留性cDC1（CD103阴性）。值得注意的是，BiCE带来的cDC1s与T细胞结合现象，只发生在肿瘤和引流淋巴结中，其他组织或免疫器官中不会出现这种现象。在使用荧光标记的BiCE处理肿瘤小鼠后，Amit团队又借助成像型流式细胞仪评估了引流淋巴结中cDC1s与T细胞结合的情况。从下图可以看出，BiCE确实加强了CLEC9A阳性cDC1和PD-1阳性T细胞在体内的物理相互作用。眼见为实，确实发生了结合随后围绕结合在一起的DC和T细胞的转录组数据来看，这种结合既导致了T细胞的活化、增殖和细胞毒性增强，也导致了cDC1的成熟。在上述研究的基础上，Amit团队在肺癌、黑色素瘤和乳腺癌小鼠模型中检验了BiCE的抗肿瘤效果。从研究结果来看，无论是作为单一疗法还是作为联合疗法的一部分，BiCE都能持续诱导有效的抗肿瘤反应，并在多种侵袭性肿瘤模型中显示出疗效，包括对传统PD-1抑制剂耐药的癌症类型。重要的是，BiCE不仅适用于原发性肿瘤，也适用于发生多处转移的肿瘤，以及还能抑制癌症的转移。BiCE的抗癌和防转移效果优异在研究的最后，Amit团队发现，BiCE之所以能起效，与IFN-γ和IL-12信号通路有密切的关系。BiCE作用机制示意图而且，他们还发现BiCE对肿瘤免疫微环境的影响与PD-1抑制剂不同，BiCE可以将肿瘤浸润淋巴细胞的组成调节为更具促炎效果的抗肿瘤表型。BiCE对肿瘤免疫微环境的影响与PD-1抑制剂不同总的来说，Amit团队认为，他们这项研究成果描述了一种以增强DC与T细胞相互作用为目的的新型抗体免疫疗法。这种疗法不仅有强大的抗肿瘤效果，还对那些对PD-1抑制剂耐药的肿瘤有活性，对于癌症的免疫治疗是一种重要的补充。期待BiCE给癌症免疫治疗注入新的活力，让更多癌症患者从免疫治疗中获益。参考文献：[1].Liu L, Chen J, Bae J, et al. Rejuvenation of tumour-specific T cells through bispecific antibodies targeting PD-L1 on dendritic cells. Nat Biomed Eng. 2021;5(11):1261-1273. doi:10.1038/s41551-021-00800-2[2].Shapir Itai Y, Barboy O, Salomon R, et al. Bispecific dendritic-T cell engager potentiates anti-tumor immunity. Cell. 2024;187(2):375-389.e18. doi:10.1016/j.cell.2023.12.011本文作者丨BioTalker

免疫疗法

2023-06-07

·FierceBiotech

FibroGen faces more trouble in clinic as DMD drug fails phase 3 trial

The trial was the first in a quiver of phase 3 studies for pamrevlumab due to read out over the coming year. FibroGen has now extended its clinical woes into a second month. After a phase 3 fail last month for Evrenzo dashed any remaining hopes of getting the oral anemia drug to market in the U.S., the biotech’s Duchenne muscular dystrophy (DMD) candidate has now flunked a late-stage study. The LELANTOS-1 trial saw 99 participants aged 12 years and older with non-ambulatory DMD given either the drug, called pamrevlumab, or placebo in combination with systemic corticosteroids. The study didn’t meet the primary endpoint as measured by a score to test the functioning of patients’ arms when measured at Week 52. “While disappointed with these results, we look forward to sharing the data at a future medical conference to contribute towards the understanding of this devastating disease,” FibroGen CEO Enrique Conterno said in the relatively sparse press release this morning. No mention was made of the failure's impact, if any, on the wider pamrevlumab program. In DMD alone, there is another phase 3 trial, the 70-person LELANTOS-2 study, due to read out in the third quarter of the year. Then there’s idiopathic pulmonary fibrosis (IPF). Pamrevlumab was hailed as a potential blockbuster back in 2017 when the company posted phase 2 data suggesting the anti-connective tissue growth factor antibody might be able to muscle in on the lucrative IPF market. Two ongoing phase 3 studies are due to read out in the third quarter of this year and mid-2024, respectively. FibroGen is even studying pamrevlumab in locally advanced unresectable pancreatic cancer, with a readout from a phase 3 study expected in the first half of next year. Despite the numerous clinical avenues being explored, today’s news means that both of FibroGen’s lead assets have struggled to prove their worth recently. While Evrenzo has failed to convince U.S. regulators, the anemia drug at least has the green light in China. The company did add another clinical contender to its portfolio last month in the form of a phase 1 antibody-drug conjugate for prostate cancer and multiple myeloma, which was acquired from Fortis. Before the year is up, FibroGen also plans to seek FDA permission to launch trials of two preclinical candidates: an anti-Gal9 antibody and an anti-CCR8 antibody.

临床3期临床2期临床结果并购抗体药物偶联物

100 项与 Anti-CLEC9A antibody(Monash University/University of Queensland) 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
感染	药物发现	澳大利亚	Monash University	2022-04-14
感染	药物发现	澳大利亚	The University of Queensland	2022-04-14
炎症	药物发现	澳大利亚	Monash University	2022-04-14
炎症	药物发现	澳大利亚	The University of Queensland	2022-04-14
肿瘤	药物发现	澳大利亚	Monash University	2022-04-14
肿瘤	药物发现	澳大利亚	The University of Queensland	2022-04-14