更新于：2024-05-01

BDCA2

C型凝集素结构域家族4

更新于：2024-05-01

基本信息

别名

血树突状细胞抗原2、BDCA-2、BDCA2

+ [12]

简介

Lectin-type cell surface receptor which may play a role in antigen capturing by dendritic cells (PubMed:11748283, PubMed:21880719, PubMed:25995448). Specifically recognizes non-sialylated galactose-terminated biantennary glycans containing the trisaccharide epitope Gal(beta1-3/4)GlcNAc(beta1-2)Man (PubMed:21880719, PubMed:25995448). Binds to serum IgG (PubMed:25995448). Efficiently targets ligand into antigen-processing and peptide-loading compartments for presentation to T-cells (PubMed:11748283). May mediate potent inhibition of induction of IFN-alpha/beta expression in plasmacytoid dendritic cells (PubMed:11748283, PubMed:21880719). May act as a signaling receptor that activates protein-tyrosine kinases and mobilizes intracellular calcium (PubMed:11748283).

关联

项与 BDCA2 相关的药物

Litifilimab

靶点

BDCA2

作用机制

BDCA2调节剂

在研机构

Biogen Idec Research Ltd. [+2]

原研机构

Biogen, Inc.

在研适应症

皮肤红斑狼疮 [+2]

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

DB-2304

靶点

BDCA2 x GR

作用机制

BDCA2抑制剂 [+1]

在研机构

映恩生物制药（苏州）有限公司

原研机构

映恩生物制药（苏州）有限公司

在研适应症

自身免疫性疾病

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

ANB-102

靶点

BDCA2

作用机制

BDCA2调节剂

在研机构

AnaptysBio, Inc. [+1]

原研机构

Centessa Pharmaceuticals Plc

在研适应症-

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 BDCA2 相关的临床试验

CTR20231573 / Recruiting临床3期

一项在活动性系统性红斑狼疮成年受试者中评价 BIIB059 持续安全性和有效性的多中心，随机，剂量设盲的III期长程扩展研究

本研究为一项多中心、随机、平行组、剂量设盲、III 期 LTE 研究。将在已完成研究 230LE303 或研究 230LE304（在本研究方案中称为“III 期母研究”）的持续 52 周研究治疗的受试者中开展本研究。

开始日期2024-04-22

申办/合作机构

渤健生物科技（上海）有限公司

[+2]

NCT06044337 / Enrolling by invitation临床3期

A Multicenter, Open-Label, Single-Arm, Phase 3, Long-Term Extension Study to Evaluate Continuous Safety and Efficacy of BIIB059 (Litifilimab) in Adult Participants With Active Subacute Cutaneous Lupus Erythematosus and/or Chronic Cutaneous Lupus Erythematosus With or Without Systemic Manifestations and Refractory and/or Intolerant to Antimalarial Therapy

The primary objective of the study is to evaluate the long-term safety and tolerability BIIB059 (litifilimab) in participants who completed the parent study 230LE301 (NCT05531565) with active subacute CLE and/or chronic CLE with or without systemic manifestations and refractory and/or intolerant to antimalarial therapy.
The secondary objectives of the study are to evaluate the long-term effect of litifilimab on disease activity and the effect of litifilimab in preventing disease damage in participants with active subacute CLE and/or chronic CLE with or without systemic manifestations and refractory and/or intolerant to antimalarials; to evaluate the long-term effect of litifilimab on preventing lupus flare in participants with CLE with systemic lupus erythematosus (SLE); to assess long-term use of oral corticosteroid (OCS) in participants receiving litifilimab treatment; to assess the impact of litifilimab on participant-reported health-related quality of life (HRQoL); to evaluate long-term effect of litifilimab on laboratory parameters; to evaluate the immunogenicity and pharmacokinetics (PK) of litifilimab.

开始日期2023-10-03

申办/合作机构

Biogen, Inc.

EUCTR2021-006378-22-BE / Unknown status临床3期

A Multicenter, Randomized, Dose-Blind, Phase 3 Long-Term Extension Study to Evaluate Continuous Safety and Efficacy of Litifilimab (BIIB059) in Adult Participants with Active Systemic Lupus Erythematosus - EMERALD

开始日期2023-09-18

申办/合作机构

Biogen Idec Research Ltd.

100 项与 BDCA2 相关的临床结果

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100 项与 BDCA2 相关的转化医学

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0 项与 BDCA2 相关的专利（医药）

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411

项与 BDCA2 相关的文献（医药）

2024-01-01·Journal of inflammation research

Pre-Implant Immune Status is Associated with Infection Risk After Left Ventricular Assist Device Implantation.

Article

作者: Maja-Theresa Dieterlen ; Eva Katharina Messer ; Kristin Klaeske ; Franz Sieg ; Sandra Eifert ; Josephina Haunschild ; Khalil Jawad ; Diyar Saeed ; Alexey Dashkevich ; Michael Andrew Borger

Purpose:

Infection is the most common complication after left ventricular assist device (LVAD) implantation. The immune status of LVAD patients is relevant for the incidence and severity of infection, but it is unknown if there is a predisposing immune status prior to LVAD implantation that contributes to an increased risk for infection in the post-implant period. We analyzed the pre-LVAD immune status in patients with infection within 3 months after LVAD implantation in comparison to infection-free patients.

Patients and Methods:

Fifty-four consecutive LVAD patients were included in this study. According to their infectious history in the first 3 months after LVAD implantation, these patients were grouped into an infection (n=23) and an infection-free group (n=31). Pre-LVAD blood samples were obtained for flow cytometric analysis of immunological parameters including B cells, subsets of T, dendritic and natural killer cells. Patient-specific, clinical and laboratory data were recorded.

Results:

Blood count analysis prior to LVAD implantation showed comparable counts of erythrocytes (p=0.19), platelets (p=0.33) and leukocytes (p=0.50) between patients with infection and infection-free patients in the post-implant period. Patients with infection in the first 3 months after LVAD implantation had lower concentrations of lymphocytes (p=0.02). Forty percent of the patients with infection showed more often pre-LVAD neutrophil-to-lymphocyte ratios (NLR) >7 than patients without infection in the first 3 months after LVAD implantation (14%, p=0.05). Patients with infection already had lower percentages of CD3⁺ T cells (p=0.03), CD19⁺ B cells (p<0.01), BDCA2⁺ pDCs (p=0.03) and BDCA4⁺ plasmacytoid DCs (pDCs) (p=0.05) prior to LVAD implantation than infection-free patients.

Conclusion:

Our results demonstrated that patients with infection in the early post-implant period showed lower concentrations of lymphocytes, especially of CD3⁺ T cells and CD19⁺ B cells, decreased percentages of BDCA2⁺ and BDCA4⁺ pDCs, and had more often NLRs >7 indicating moderate-to-severe inflammation. Thus, we identified specific immunological changes pre-LVAD that could help to identify patients at risk for infection in the early post-implant period.

2023-11-01·Clinical and translational allergy

A robust mRNA signature obtained via recursive ensemble feature selection predicts the responsiveness of omalizumab in moderate-to-severe asthma.

Article

作者: Sarah Kidwai ; Pietro Barbiero ; Irma Meijerman ; Alberto Tonda ; Paula Perez-Pardo ; Pietro Lio ; Anke H van der Maitland-Zee ; Daniel L Oberski ; Aletta D Kraneveld ; Alejandro Lopez-Rincon

BACKGROUND:

Not being well controlled by therapy with inhaled corticosteroids and long-acting β2 agonist bronchodilators is a major concern for severe-asthma patients. The current treatment option for these patients is the use of biologicals such as anti-IgE treatment, omalizumab, as an add-on therapy. Despite the accepted use of omalizumab, patients do not always benefit from it. Therefore, there is a need to identify reliable biomarkers as predictors of omalizumab response.

METHODS:

Two novel computational algorithms, machine-learning based Recursive Ensemble Feature Selection (REFS) and rule-based algorithm Logic Explainable Networks (LEN), were used on open accessible mRNA expression data from moderate-to-severe asthma patients to identify genes as predictors of omalizumab response.

RESULTS:

With REFS, the number of features was reduced from 28,402 genes to 5 genes while obtaining a cross-validated accuracy of 0.975. The 5 responsiveness predictive genes encode the following proteins: Coiled-coil domain- containing protein 113 (CCDC113), Solute Carrier Family 26 Member 8 (SLC26A), Protein Phosphatase 1 Regulatory Subunit 3D (PPP1R3D), C-Type lectin Domain Family 4 member C (CLEC4C) and LOC100131780 (not annotated). The LEN algorithm found 4 identical genes with REFS: CCDC113, SLC26A8 PPP1R3D and LOC100131780. Literature research showed that the 4 identified responsiveness predicting genes are associated with mucosal immunity, cell metabolism, and airway remodeling.

CONCLUSION AND CLINICAL RELEVANCE:

Both computational methods show 4 identical genes as predictors of omalizumab response in moderate-to-severe asthma patients. The obtained high accuracy indicates that our approach has potential in clinical settings. Future studies in relevant cohort data should validate our computational approach.

2023-10-25·Immunotherapy

The development of litifilimab (BIIB 059) for cutaneous and systemic lupus erythematosus.

Review

作者: Young Min Cho ; Richard Furie

This review describes the litifilimab (BIIB 059) development program to date for systemic lupus erythematosus (SLE) and cutaneous lupus erythematosus (CLE). Plasmacytoid dendritic cells (pDCs), major producers of type I interferons (IFN-I), play a key role in SLE pathogenesis. Litifilimab, a humanized monoclonal antibody, binds to BDCA2, a protein uniquely expressed on pDCs. The consequence of BDCA2 ligation is the inhibition of IFN-I as well as IFN-III, cytokine and chemokine production. Phase I and II LILAC trial parts A and B achieved primary end points in SLE and CLE patients, confirming the importance of pDCs and IFN-I in SLE and CLE. Litifilimab is currently being evaluated in phase III trials in both SLE and CLE.

项与 BDCA2 相关的新闻（医药）

2024-04-02

·佰傲谷BioValley

自身免疫性疾病“微环境”

不少自身免疫病都伴有皮肤病变（简述26种自身免疫性疾病）。作为免疫系统的第一道屏障，皮肤也存在影响疾病进展的免疫微环境。人类和小鼠皮肤中的免疫细胞类型Mucosal Immunol 15, 551–561 (2022)皮肤中的先天免疫细胞群皮肤中的APC包括：肥大细胞，尤其是在肢端部位。皮肤巨噬细胞：包括胚胎来源和招募的单核细胞衍生亚群。先天淋巴细胞(ILC)：1型(如NK细胞)，2型和3型ILC都存在于皮肤中，但ILC2尤其普遍。虽然皮肤ILC与其他粘膜组织中的ILC一样，主要是局部维持和扩张的组织驻留型细胞，但它们表达独特的受体模式，并且特别依赖于IL-18和TSLP的激活和功能。Immunity. 2021 Oct 12;54(10):2305-2320.e11.真皮中的其他DC亚群包括：经典树突状细胞(cDC)：cDC1型：在人皮肤中表达CD141，在小鼠皮肤中表达CD103；cDC2型：在人皮肤中表达CD1c，在小鼠皮肤中表达CD11b。在小鼠真皮中，也有CD103- CD11b-的“双阴性”DC细胞亚群。CD123+浆细胞样DC：在健康皮肤中的含量很少，但在各种疾病的情况下可以显着增加。单核细胞来源的DC细胞(moDCs)：经典单核细胞在进入组织后经过获得II类表达分化而来。人皮肤中表达CD14,小鼠皮肤中表达CD11b和CD64。朗格汉斯细胞(LCs)：主要存在于表皮中，通过延伸其树突以捕获皮肤表面附近的抗原。最近的研究表明，LC实际上是胚胎来源的组织驻留巨噬细胞的一个子集。其特点包括：在皮肤炎症期间，骨髓来源的单核细胞有助于增强朗格汉斯细胞的免疫特性。朗格汉斯细胞已被证明可以促进皮肤中的效应和调节性T细胞反应。最近研究鉴定了两个人类皮肤中的朗格汉斯细胞亚群LC1和LC2，二者的主要分化调节途径之一是EGR1和Notch信号。LC1在炎症微环境下保持稳定，而LC2容易被激活并表现出免疫抑制分子的表达升高。皮肤淋巴细胞：皮肤也是T细胞的密集储存库，整个表皮中约含有2×10^10个。以组织驻留的记忆亚型居多。在小鼠皮肤中，Vγ5Vδ1树突状表皮T细胞（DETC）在妊娠晚期就驻留在表皮中，与朗格汉斯细胞形成稳定的相互作用并产生细胞因子，有助于角质形成细胞的稳态增殖和伤口愈合。人类表皮缺乏DETC，但含有更多的CD8+CD103+ αβ T细胞群，这些细胞可能执行类似的功能。CD4+T细胞占人和小鼠皮肤中αβ T细胞的大部分。这些细胞优先存在于真皮中，但也可以存在于表皮和皮下。具有驻留记忆表型的Tregs占健康成人皮肤CD4+T细胞群的10-30%。皮肤Tregs中可能包含相当比例的胸腺来源Tregs。真皮中还含有丰富的非经典淋巴细胞亚群：真皮γδ T细胞群(小鼠皮肤中比例较人更高）、粘膜相关的不变性T(MAIT)细胞等。在稳定状态下，少量中性粒细胞，单核细胞和αβ T细胞负责检查真皮中的病原体；在炎症刺激下，皮肤驻留DC、巨噬细胞前体细胞、中性粒细胞、T细胞等免疫细胞收到招募，在细胞外基质(ECM)中迅速积聚。γδ T细胞、MAIT细胞和CD4+ Th17细胞则是皮肤IL-17A的主要来源。不同于肠道免疫微环境，使用靶向生物制剂的IL-17与上皮完整性的损害无关。抗IL-17疗法现在是治疗银屑病的主要手段。角质形成细胞则在表皮免疫微环境中表达几种不同的模式识别受体，并在炎症时产生多种细胞因子，包括胸腺基质淋巴生成素(TSLP)、TNF和IL-33等IL-1家族成员。这些细胞因子是激活皮肤免疫细胞和免疫细胞募集到皮肤所必需的。自身免疫病的表皮免疫微环境影响皮肤炎症伴有皮肤先天免疫细胞的显着变化，包括：巨噬细胞、树突状细胞、肥大细胞和ILC显著扩张；新细胞亚群募集，例如嗜酸性粒细胞和中性粒细胞；细胞活化，导致关键表面标志物表达模式改变。在不同类型的自身免疫病中，皮肤中可能存在的APC也有所不同。接触性超敏反应(CHS)：皮肤DC细胞、肥大细胞、嗜碱性粒细胞、血液内皮细胞、抗辐射细胞或朗格汉斯细胞；移植物宿主病(GvHD)：朗格汉斯细胞或角质细胞；银屑病：皮肤DC或朗格汉斯细胞。CHS：在CHS的诱发中，真皮DC是其中最重要的APC。真皮DC捕获的半抗原被呈现给皮肤中的效应T细胞。活化的效应T细胞产生IFNγ并引起皮肤炎症。同时，角质形成细胞收到诱导产生IL-1α，从而激活位于毛细血管后小静脉周围的M2型巨噬细胞。活化的巨噬细胞产生CXCL2，促进真皮DC的积累。银屑病：近期研究发现，表皮免疫微环境(epidermal immune microenvironment)在银屑病的发展中起主导作用。银屑病真皮中，表达CD1c和CD11b的DC2s在预启动阶段迁移到病灶周围皮肤区域，迅速取代EpCAM+++++CD11c low LC细胞，并引发炎症。表皮CD141 cDC1、CD1c cDC2、CD14 moDC和BDCA2 pDC可协调银屑病炎症。CCR2+ CD11c+hi LC在银屑病表皮中释放IL-23。CD5 T细胞在银屑病表皮和真皮中产生IL-17A和TNF-α的能力增强。CD4+CD25+Foxp3+Treg被认为在维持免疫稳态和通过抑制免疫应答调节局部组织炎症方面起重要作用。在银屑病中，Treg抑制功能受损导致辅助性T17/Treg平衡改变。不过Tregs在银屑病发病机制中的确切功能仍不清楚。Cell Mol Immunol (2022)参考文献：1.Zhang, C., Merana, G.R., Harris-Tryon, T. et al. Skin immunity: dissecting the complex biology of our body’s outer barrier. Mucosal Immunol 15, 551–561 (2022). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41385-022-00505-y2.Zhou, Y., Xu, F., Chen, XY. et al. The epidermal immune microenvironment plays a dominant role in psoriasis development, as revealed by mass cytometry. Cell Mol Immunol (2022). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41423-022-00940-83.Kabashima, K., Honda, T., Ginhoux, F. et al. The immunological anatomy of the skin. Nat Rev Immunol 19, 19–30 (2019). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41577-018-0084-54.Liu X, Zhu R, Luo Y, Wang S, Zhao Y, Qiu Z, Zhang Y, Liu X, Yao X, Li X, Li W. Distinct human Langerhans cell subsets orchestrate reciprocal functions and require different developmental regulation. Immunity. 2021 Oct 12;54(10):2305-2320.e11. doi: 10.1016/j.immuni.2021.08.012. Epub 2021 Sep 10. PMID: 34508661.本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处···

临床研究免疫疗法细胞疗法

2024-02-23

·生物制品圈

GSK最新发文|如何开发靶向免疫细胞的mRNA疫苗递送系统？

导读：随着对适应性免疫在细胞和分子水平上的认识，靶向免疫细胞的抗原因其可能提高疫苗效力和/或调节免疫反应质量，同时减少脱靶效应，被证明是开发创新、强效疫苗的成功策略。随着mRNA疫苗的发展，近几年已经探索了几种将包裹mRNA的纳米颗粒递送系统靶向免疫细胞（树突状细胞DC）的方法，DC是最有效的抗原呈递细胞，也是B细胞和T细胞免疫的关键介质，被认为是细胞特异性抗原递送的理想靶标。那么如何设计mRNA疫苗递送系统以靶向免疫细胞呢？2023年11月，GSK团队在Front Immunol期刊发表综述文章：《Straight to the point: targeted mRNA-delivery to immune cells for improved vaccine design》。文章汇总了mRNA定向递送免疫系统的潜在特异性靶点、靶向受体-配体类别以及递送系统的研究进展。一、免疫细胞靶向由于常规疫苗（抗原、灭活病原体）开发周期长（5-10年），针对新发和再发疾病的疫苗开发难度大，科学家们致力于探索新的疫苗平台，最近，mRNA疫苗在设计和疗效方面有较大突破，其之所以能脱颖而出，与以下特性有关：1、安全性：mRNA的非感染性和非整合性避免感染或插入诱变的潜在风险。2、稳定性：mRNA疫苗可通过纳米载体（如LNPs）实现体内递送，使其免于降解、快速摄取和细胞质递送，避免抗载体免疫。3、高产量：由于体外转录反应的高产量，mRNA疫苗具有经济高效、可扩展生产的潜力。4、可修饰性：可进行快速修饰调节半衰期和免疫原性特征，用于个性化治疗或紧急适应新出现的病原体。但同时mRNA疫苗具有以下不足：1、潜在的脱靶效应：肌肉注射后，会有少部分到达血流，最终主要进入肝脏和脾脏，出现脱靶效应。2、非特异性：mRNA-LNPs的给药会诱导中性粒细胞、单核细胞和DCs快速和局部浸润到给药部位及引流淋巴结（LNs），但主要是单核细胞和DCs翻译mRNA并上调关键的共刺激受体（CD80和CD86）和细胞因子产生。3、针对某些蛋白（如刺突蛋白）的抗体反应持久性较短，需要连续给予加强剂量以保持对感染的保护。mRNA选择性靶向免疫细胞因可增强免疫应答、减少疫苗使用剂量、增加保护时长、最大程度减少脱靶及副作用的特性，成为解决上述问题的关键技术。而抗原呈递细胞（APCs），尤其是DCs，因其通过启动幼稚T细胞来启动适应性免疫的独特能力成为mRNA靶向递送的候选细胞。研究表明，即使在低抗原剂量下，DC靶向也能增强和加速特异性抗体反应。使用与特定细胞表面的受体特异性相互作用的配体可实现靶向，不同受体的参与会影响所诱导免疫反应的类型，从而获得特定的结果。DCs可表达多种靶向递送疫苗的受体，包括C型凝集素受体（CLRs）、Toll样受体、清道夫受体、趋化因子受体、补体受体和Fc受体等。DC靶向不仅可提高mRNA疫苗的功效，还能扩大其作用的病原体范围。除DC亚群，参与免疫反应的其他细胞类型（如巨噬细胞）也可作为靶标。图1. APC靶向LNP-mRNA作用机制二、靶细胞下表从起源、分布、特征/功能等方面对多种抗原呈递细胞（APC）进行比较：每种APC都有优点和局限性：与pDCs相比，cDCs在抗原呈递和T细胞活化方面更有效；与巨噬细胞相比，DCs因其拥有卓越的抗原呈递及从外周组织迁移到淋巴结的能力而具有更强引发抗原特异性免疫反应的能力，使其在进行靶向递送方面更具优势。最终靶向何种APC还取决于要靶向的病原体或抗原的特征，多种APCs（如DCs和巨噬细胞）的组合可引发协同效应并产生更强大和多功能的免疫反应。三、靶受体免疫反应的类型和程度取决于捕获抗原的环境，包括用于内化的受体。因此，靶向递送平台的成功取决于配体-受体对的正确选择。3.1 C型凝集素（CLRs）受体3.1.1 CLRs的通性CLRs是由1,000多种蛋白质组成的超家族，因其在各种免疫细胞（包括DCs、巨噬细胞和中性粒细胞等）表面大量表达，并在识别自身和非自身抗原、内化、抗原加工、启动免疫反应、调节免疫细胞间相互作用中发挥作用，被作为靶向抗原和mRNA递送的靶标：CLRs具有一个保守的结构基序-碳水化合物识别结构域（CRD），通过与保守的钙螯合结合位点的相互作用来识别病原体（病毒、细菌和真菌）相关的碳水化合物结构，促进识别和吞噬作用；CLRs信号转导可分为两组：第一组通过基于整合免疫受体酪氨酸的激活（ITAM）样基序（Clec-2、Dectin-1）转导细胞内信号，或通过与携带ITAM的FcRγ接头分子（Dectin-2、Mincle、BDCA-2）结合转导细胞内信号。磷酸化后，ITAM 基序募集并激活 Syk，Syk通过激活转录因子NF-kB复合体的亚基来诱导促炎细胞因子的转录。第二组CLRs在其胞浆末端具有基于免疫受体酪氨酸的抑制（ITIM）基序（例如 MICL）。3.1.2 甘露糖受体甘露糖受体（CD206， MR）为巨噬细胞和DCs表达的内吞受体，介导甘露糖苷（从简单甘露糖到高级甘露聚糖结构）以及岩藻糖和硫酸化LacdiNAc的可溶性配体的交叉呈递，上述特性使基于甘露糖的靶向成为最常见的CLR靶向策略之一。2006年White等人在体外模型中使用甘露糖基化脂质体来增加单核细胞来源的DCs（moDCs）对OVA的摄取。大量报告表明，基于甘露糖的策略通过受体介导的机制增加了免疫细胞中mRNA疫苗的内化和转染。2011年首次报道了MR靶向癌症疫苗的临床试验，但MR靶向mRNA疫苗的临床活性尚不清楚。3.1.3 其他C型凝集素1、DC-SIGN：钙依赖型，存在于人的DCs和巨噬细胞亚群上，可结合高甘露糖基化糖缀合物和含岩藻糖的抗原，通过促进T细胞粘附到DC表面以查找肽抗原的存在来介导DC-T细胞相互作用。DC-SIGN会诱导细胞内信号转导，从而调节其他病原体识别受体PRRs（如TLRs）的信号转导。2、DEC-205（CD205）：在DCs、单核细胞和LCs上表达，也在B细胞、T细胞和NK细胞上低水平表达，具有识别凋亡和坏死信号、参与内吞作用并增加MHC II呈递的功能。大多数DC205靶向依赖于抗体或抗体片段的使用，从而产生有效的DC靶向和增强的抗原交叉呈递，2011年进行了针对抗HIV DEC-205靶向疫苗的临床试验。3、Dectin-1：由DCs、巨噬细胞、单核细胞、中性粒细胞和T细胞亚群表达，能特异性识别具有不同亲和力的可溶性和颗粒性β（1-3）和/或β（1-6）连接葡聚糖，通过肌动蛋白依赖性吞噬作用促进颗粒摄取并通过ITAM样基序参与细胞活化，因可以与CD4+和CD8+T细胞结合并促进增殖被认为是一种共刺激分子。4、Langerin（CD207）：由LCs、真皮DCs和其他DCs亚型表达，已成功使用抗体或小分子糖作为靶向配体在体外进行LC靶向，Wamhoff等人发现了一种Langerin拟糖配体，并使用功能化脂质体证明了其对Langerin+细胞的选择性。Schulze等人用这种Langerin配体在体外选择性地将纳米颗粒（脂质体）靶向人LCs，该配体可用于功能化封装药物、抗原或毒素的纳米颗粒以递送至LCs中。5、DNGR-1（Clec9a）和MGL（Clec10a）：DNGR-1/Clec9a在人cDC1上选择性表达。与该受体的特异性相互作用可促进非人灵长类动物的体液免疫，最近研究发现DNGR-1特异性肽可将纳米颗粒靶向Clec9a+ DC。MGL在人cDC2（CD1c+ DCs）上特异性表达，选择性地结合GalNAc末端和具有不同糖基化谱的粘蛋白-1肽。Heger等人发现，使用Clec10a结合糖肽，可以选择性靶向PBMCs中的CD1c+细胞（cDC2），但未观察到单独的Clec10的配体可诱导CD1c+ DCs的激活或细胞因子分泌。6、hDCIR（Clec4a）：存在于外周血中的CD14+单核细胞、CD15+粒细胞、所有DC亚群（包括pDCs）和B细胞上，T细胞中未发现，使用抗体将抗原靶向DCIR可增加LCs、血液mDCs和pDCs的交叉呈递，并增强体外人细胞中CD8+ T细胞触发。3.2 用于mRNA靶向递送的其他受体1、Toll样受体（TLRs）：由先天免疫系统细胞（如巨噬细胞和DCs）、适应性免疫细胞亚群表达，通过识别病原体相关分子模式PAMPs在先天免疫系统中发挥关键作用，研究使用Pam3CSK4（一种TLR-2激动剂）作为靶向配体将纳米颗粒靶向DCs。2、X-C基序趋化因子受体1（XCR1）：可识别XCL1的趋化因子受体，在cDC1上选择性表达。Fossum等人研究Clec9a、DEC-205和XCR-1作为靶标，使用编码与抗原融合的单链可变片段（scVf）的DNA疫苗注射到小鼠体内，发现靶向XCR-1导致脾脏和肺中IFN-γ+CD8+ T细胞反应增强，细胞毒性更强，尽管Clec9a和XCR1都是cDC1特异性的，但导致不同的结果，因此不仅细胞亚型，受体本身也决定了靶向的结果和疗效。表1 免疫细胞靶向案例、靶向策略和结果四、纳米颗粒作为靶向mRNA递送载体将mRNA与载体结合以保护其免于降解并实现胞内递送。目前输送系统简单分为病毒和非病毒载体。病毒载体利用其自然进化的能力将遗传物质有效地转移到细胞中，实现高效率翻译，但其自身的趋向性并不总是满足治疗需求，且诱导的免疫反应可转化为反应原性损害治疗效果。目前纳米颗粒（特别是脂质纳米颗粒LNP）为首选的非病毒载体，提供了定制其特性以优化其作为转染剂性能的可能性。脂质纳米颗粒（LNPs）已从脂质体和脂质复合体进化为更有效的mRNA载体，出现了可电离脂质，其优势在于：1、可电离脂质在酸性pH值下带正电，在生理pH值下带中性电，该特性大大改善了永久性阳离子脂质的固有缺点，如耐受性差和细胞毒性；2、可电离脂质在内体中酸化后，胺基团被质子化并促进氯离子转运以平衡膜电荷和渗透压，直到膜被破坏并将遗传物质递送到胞质溶胶中；3、通过增加可电离脂质疏水尾部的不饱和度以及调整其pKa，可增加内体逃逸，增强疫苗效力；4、可电离脂质能实现高速率mRNA包封，由于生产过程中水相的pH值较低，可电离脂质带正电，从而促进了与带负电荷的mRNA骨架的相互作用。LNPs另一个成分是聚乙二醇化脂质，由亲水性PEG聚合物与疏水脂质偶联而成。聚乙二醇化脂质可阻止调理素结合，增加LNP循环时间并防止颗粒融合。通过改变PEG脂质锚定长度，可调整其从LNP表面的脱落速率，对促进细胞摄取和内体逃逸至关重要。另外LNPs中的磷脂和胆固醇有助于mRNA包封及增强稳定性。对LNPs脂质成分和/或比例进行多种修饰，实现其优先在特定器官中积累的特性，Goswami等人表明，甘露糖化胆固醇可改善抗RSV自扩增mRNA疫苗（SAM）的内化和效力，一些MR靶向siRNA的例子（配体直接连接到siRNA 或siRNA包封颗粒）也被报道。图2 LNP 结构、组成和靶向配体加入策略五、结论靶向先天免疫相关细胞上的特异性受体可以产生针对疫苗量身定制的更强大、更持久的免疫反应，不同先天免疫细胞亚群的联合靶向策略更令人期待，因为它们在免疫反应中起着独特而核心的作用。如巨噬细胞驱动炎症反应，而树突状细胞在抗原呈递给T细胞中起关键作用，若同时靶向两种细胞类型可能有助于启动改善的抗原特异性免疫反应。需要进一步的研究来识别不同细胞类型中潜在的共同关键受体，或配制具有多种靶向配体组合的LNPs。对于开发RNA递送载体，应在载体配方步骤中考虑组分的相容性，以及保持有效的内体逃逸和充分的多价配体展示的必要性。eGFP mRNA和mCherry mRNA在293T细胞中实现高表达参考文献[1] Clemente B, Denis M, Silveira CP, Schiavetti F, Brazzoli M, Stranges D. Straight to the point: targeted mRNA-delivery to immune cells for improved vaccine design. Front Immunol. 2023 Nov 27;14:1294929. doi: 10.3389/fimmu.2023.1294929.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有转载文章系出于传递更多信息之目的，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

2023-11-28

·GlobeNewswire-Health Care

Anaptys Expands Immune Cell Modulator Pipeline with Exclusive License to BDCA2 Modulator Antibody Portfolio from Centessa Pharmaceuticals

Anaptys licenses exclusive global development and commercialization rights to a potential best-in-class BDCA2 modulator portfolio IND filing to support clinical development of ANB101 in autoimmune and inflammatory diseases expected in H2 2024 Reiterating year-end 2023 cash and investments of $400 to $410 million and cash runway through year-end 2026 AnaptysBio, Inc. (Nasdaq: ANAB), a clinical-stage biotechnology company focused on delivering innovative immunology therapeutics, today announced an exclusive license agreement for Centessa Pharmaceuticals’ (NASDAQ: CNTA) blood dendritic cell antigen 2 (BDCA2) modulator antibody portfolio, including lead asset CBS004 and related family of backup antibodies, for the treatment of autoimmune and inflammatory diseases. Anaptys anticipates filing an IND application for CBS004, which will be renamed ANB101, in H2 2024. “Acquiring the rights to this BDCA2 modulator portfolio, which specifically targets plasmacytoid dendritic cells, known to be key drivers of interferon secretion and antigen presentation, complements our portfolio of best-in-class immune cell modulators to drive differentiated clinical outcomes in systemic, heterogeneous autoimmune and inflammatory diseases,” said Daniel Faga, president and chief executive officer of Anaptys. “We now plan to file two INDs in 2024: ANB101 in H2 2024 and ANB033, our CD122 antagonist, in H1 2024.” “We are pleased to enter into this agreement with Anaptys, which enables the continued advancement of Centessa’s BDCA2 modulators,” said Saurabh Saha, M.D., Ph.D., chief executive officer of Centessa. “With their focus on developing immune cell modulators, Anaptys is well positioned to further the research and development of this program in autoimmune and inflammatory diseases.” Plasmacytoid dendritic cells (pDCs) are a key upstream node in the inflammatory cascade that serve as a bridge between innate and adaptive immunity. They have been shown to be prolific secretors of type I interferons, which drive activation of a variety of downstream cell types including T cells and monocytes. Together with their ability to present antigens to the adaptive immune system, this creates a pro-inflammatory environment for the establishment and perpetuation of autoimmune pathology. BDCA2 is a molecule specifically expressed on pDCs, a class of immune cells which, while found in relatively small numbers in healthy patients, are enriched in patients with a variety of inflammatory diseases, that is critical to the regulation of toll-like receptor signaling and interferon secretion. BDCA2 has been implicated in the pathophysiology of systemic lupus erythematosus (SLE), where there exists mechanistic clinical proof of concept for pDC modulation. ANB101 is a potentially best-in-class BDCA2 modulator antibody that targets pDCs and potently inhibits interferon secretion and modulates antigen presentation for the treatment of autoimmune and inflammatory diseases. Under the terms of the agreement, Anaptys will receive from Centessa Pharmaceuticals an exclusive, global license for ANB101. Anaptys will also receive the same rights to ANB102, an extended half-life BDCA2 modulator with the potential to enable quarterly or less frequent dosing. ANB101 has successfully completed IND-enabling studies and manufacturing scale-up. Anaptys will assume responsibility for all future clinical development. In exchange, Anaptys will pay Centessa a one-time upfront cash payment of $7 million, inclusive of a one-time cash payment of $3 million for manufactured and released GMP supply of ANB101. Centessa is eligible to receive an additional development milestone payment and low single-digit royalties on global net sales. Anaptys is a clinical-stage biotechnology company focused on delivering innovative immunology therapeutics. It is developing immune cell modulators, including two checkpoint agonists for autoimmune and inflammatory disease: rosnilimab, its PD-1 agonist, in a Phase 2b trial for the treatment of rheumatoid arthritis and in a Phase 2 trial for the treatment of ulcerative colitis; and ANB032, its BTLA agonist, in a Phase 2b trial for the treatment of atopic dermatitis. Its preclinical immune cell modulator portfolio includes ANB033, an anti-CD122 antagonist antibody, and ANB101, a BDCA2 modulator antibody, for the treatment of autoimmune and inflammatory diseases. In addition, Anaptys has developed two cytokine antagonists available for out-licensing: imsidolimab, an anti-IL-36R antagonist, in Phase 3 for the treatment of generalized pustular psoriasis, or GPP, and etokimab, an anti-IL-33 antagonist for the treatment of respiratory disorders that is Phase 2/3 ready. Anaptys has also discovered multiple therapeutic antibodies licensed to GSK in a financial collaboration for immuno-oncology, including an anti-PD-1 antagonist antibody (Jemperli (dostarlimab-gxly)) and an anti-TIM-3 antagonist antibody (cobolimab, GSK4069889). To learn more, visit www.AnaptysBio.com or follow us on LinkedIn and X. The content above comes from the network. if any infringement, please contact us to modify.