更新于：2024-05-01

Siglec-8

唾液酸结合免疫球蛋白样凝集素-8

更新于：2024-05-01

基本信息

别名

MGC59785、SAF-2、SAF2

+ [7]

简介

Putative adhesion molecule that mediates sialic-acid dependent binding to red blood cells (PubMed:10856141, PubMed:10625619). Preferentially binds to alpha-2,3-linked sialic acid. Also binds to alpha-2,6-linked sialic acid. The sialic acid recognition site may be masked by cis interactions with sialic acids on the same cell surface (PubMed:10625619). Recognizes simultaneously epitopes having a terminal N-acetylneuraminic acid (sialic acid) and an underlying 6-O-sulfated galactose. Preferentially binds to Gal-6-sulfated sialyl-Lewis X glycan epitopes (PubMed:27357658).

关联

项与 Siglec-8 相关的药物

Antolimab

靶点

Siglec-8

作用机制

Siglec-8抑制剂 [+1]

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

ALX-009

靶点

Siglec-10 x Siglec-15 x Siglec-8

作用机制

Siglec-10拮抗剂 [+3]

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1期

首次获批国家/地区-

首次获批日期1800-01-20

AK-001

靶点

Siglec-8

作用机制

Siglec-8抑制剂 [+1]

在研机构-

原研机构

Allakos, Inc.

在研适应症-

非在研适应症

特应性皮炎 [+1]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

项与 Siglec-8 相关的临床试验

NCT05528861 / Active, not recruiting临床2期

A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Lirentelimab in Adult Subjects With H-1 Antihistamine Refractory Chronic Spontaneous Urticaria

This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of subcutaneous lirentelimab (AK002) in adult subjects with H-1 antihistamine refractory chronic spontaneous urticaria. Subjects who complete the randomized, double-blind, placebo-controlled treatment period may have the option to enroll in an open-label extension period and receive up to 6 doses of subcutaneous lirentelimab.

开始日期2022-10-26

申办/合作机构

Allakos, Inc.

NCT05155085 / Active, not recruiting临床2期

A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Subcutaneous Lirentelimab in Adult Subjects With Moderate-to-Severe Atopic Dermatitis Inadequately Controlled by Topical Treatments

This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of subcutaneous lirentelimab (AK002), given every 2 weeks for 7 doses, in adult subjects with moderate-to-severe AD inadequately controlled by topical treatments. Subjects who complete the randomized, double-blind, placebo-controlled treatment period may have the option to enroll in an open-label extension period and receive up to 7 doses of subcutaneous lirentelimab.

开始日期2022-06-27

申办/合作机构

Allakos, Inc.

NCT05152563 / Withdrawn临床3期

A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacodynamic Effect of Subcutaneous AK002 in Subjects With Moderate to Severe Eosinophilic Gastritis and/or Eosinophilic Duodenitis

This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, tolerability, and pharmacodynamic effect of subcutaneous lirentelimab (AK002), given monthly for 6 doses, in subjects with moderate to severe Eosinophilic Gastritis and/or Eosinophilic Duodenitis who have an inadequate response with, lost response to, or were intolerant to standard therapies.

开始日期2021-12-01

申办/合作机构

Allakos, Inc.

100 项与 Siglec-8 相关的临床结果

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100 项与 Siglec-8 相关的转化医学

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0 项与 Siglec-8 相关的专利（医药）

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166

项与 Siglec-8 相关的文献（医药）

2024-01-13·Current allergy and asthma reports

Mast Cell-Targeting Therapies in Mast Cell Activation Syndromes.

Review

作者: Vito Sabato ; Michiel Beyens ; Alessandro Toscano ; Athina Van Gasse ; Didier G Ebo

PURPOSE OF REVIEW:

Provide an overview of the expanding landscape of mast cell (MC)-targeting treatments in mast cell activation syndromes (MCAS).

RECENT FINDINGS:

Tyrosine-kinase inhibitors (TKIs) targeting wild-type and mutated KIT can efficiently induce MC depletion. Avapritinib and midostaurin can also temper IgE-mediated degranulation. Avapritinib has been recently approved by the FDA for the treatment of indolent systemic mastocytosis (ISM). Targeting activation pathways and inhibitory receptors is a promising therapeutic frontier. Recently, the anti Siglec-8 antibody lirentelimab showed promising results in ISM. MCAS is a heterogeneous disorder demanding a personalized therapeutic approach and, especially when presenting as anaphylaxis, has not been formally captured as outcome in prospective clinical trials with TKI. Long-term safety of TKI needs to be addressed. New drugs under investigation in diseases in which non-neoplastic MCs play a pivotal role can provide important inputs to identify new efficient and safe treatments for MCAS.

2024-01-07·Allergy

Regulation of mast cells by overlapping but distinct protein interactions of Siglec-6 and Siglec-8.

Article

作者: Wouter Korver ; Zachary Benet ; Alan Wong ; Gian Luca Negri ; Katherine Chang ; Robert Sanchez ; John Leung ; Naomi De Freitas ; Thuy Luu ; Julia Schanin ; Bradford A Youngblood

BACKGROUND:

Sialic acid-binding immunoglobulin-like lectin (Siglec)-6 and Siglec-8 are closely related mast cell (MC) receptors with broad inhibitory activity, but whose functional differences are incompletely understood.

METHODS:

Proteomic profiling using quantitative mass spectrometry was performed on primary mouse MCs to identify proteins associated with Siglec-6 and Siglec-8. For functional characterization, each receptor was evaluated biochemically and in ex vivo and in vivo inhibition models of IgE and non-IgE-mediated MC activation in Siglec-6- or Siglec-8-expressing transgenic mice.

RESULTS:

Siglec-6 and Siglec-8 were found in MCs within large complexes, interacting with 66 and 86 proteins, respectively. Strikingly, Siglec-6 and Siglec-8 interacted with a large cluster of proteins involved in IgE and non-IgE-mediated MC activation, including the high affinity IgE receptor, stem cell factor (SCF) receptor KIT/CD117, IL-4 and IL-33 receptors, and intracellular kinases LYN and JAK1. Protein interaction networks revealed Siglec-6 and Siglec-8 had overlapping yet distinct MC functions, with a potentially broader regulatory role for Siglec-6. Indeed, Siglec-6 preferentially interacted with the mature form of KIT at the cell surface, and treatment with an anti-Siglec-6 antibody significantly inhibited SCF-mediated MC activation more in comparison to targeting Siglec-8.

CONCLUSION:

These data demonstrate a central role for Siglec-6 and Siglec-8 in controlling MC activation through interactions with multiple activating receptors and key signaling molecules. Our findings suggest that Siglec-6 has a role distinct from that of Siglec-8 in regulating MC function and represents a distinct potential therapeutic target in mast cell-driven diseases.

2023-11-09·Angewandte Chemie (International ed. in English)

Tetra- and Hexavalent Siglec-8 Ligands Modulate Immune Cell Activation.

Article

作者: Gabriele Conti ; Anne Bärenwaldt ; Said Rabbani ; Mirza Sarcevic ; Xiaohua Jiang ; Oliver Schwardt ; Daniel Ricklin ; Roland J Pieters ; Heinz Läubli ; Beat Ernst ; Tobias Mühlethaler

Carbohydrate-binding proteins are generally characterized by poor affinities for their natural glycan ligands, predominantly due to the shallow and solvent-exposed binding sites. To overcome this drawback, nature has exploited multivalency to strengthen the binding by establishing multiple interactions simultaneously. The development of oligovalent structures frequently proved to be successful, not only for proteins with multiple binding sites, but also for proteins that possess a single recognition domain. Here we present the syntheses of a number of oligovalent ligands for Siglec-8, a monomeric I-type lectin found on eosinophils and mast cells, alongside the thermodynamic characterization of their binding. While the enthalpic contribution of each binding epitope was within a narrow range to the one of the monomeric ligand, the entropy penalty increases steadily with growing valency. Additionally, we observed a successful agonistic binding of the tetra- and hexavalent and, to an even larger extent, multivalent ligands to Siglec-8 on immune cells and modulation of immune cell activation. Thus, triggering a biological effect is not restricted to multivalent ligands but could be induced by low oligovalent ligands as well, whereas a monovalent ligand, despite binding with similar affinity, showed an antagonistic effect.

项与 Siglec-8 相关的新闻（医药）

2024-02-12

·GlobeNewswire-Health Care

Allakos Announces Publication Highlighting AK006 Mast Cell Inhibition

– Data provide insights on the signaling pathways involved with AK006 mast cell inhibition –– AK006 has a distinct mechanism of action that leads to broad inhibitory effects on mast cells – SAN CARLOS, Calif., Feb. 12, 2024 (GLOBE NEWSWIRE) -- Allakos Inc. (Nasdaq: ALLK), a clinical-stage biotechnology company developing therapeutics that target immunomodulatory receptors present on immune effector cells involved in allergy, inflammatory and proliferative diseases, today announced the publication of new scientific results in Allergy. The preclinical research found that AK006 (agonist Siglec-6 antibody) impacts mast cell function by interacting with multiple activating receptors and key signaling molecules. The publication titled “Regulation of Mast Cells by Overlapping but Distinct Protein Interactions of Siglec-6 and Siglec-8” details efforts to identify proteins associated with Siglec-6 and Siglec-8 in mast cells and functionally characterize these protein interaction networks using ex vivo and in vivo models of mast cell activation. The data published today add to previously published preclinical data demonstrating that AK006 inhibits multiple modes of mast activation. As detailed in the Allergy publication, proteomic profiling of mast cells revealed Siglec-6 and Siglec-8 interact with a large cluster of proteins involved in IgE and non-IgE-mediated mast cell activation, including the high affinity IgE receptor (FcεRI), IL-4 and IL-33 receptors, and intracellular kinases LYN and JAK1. Importantly, Siglec-6 was found to interact with multiple critical regulatory proteins that do not interact with Siglec-8, including stem cell factor (SCF) receptor KIT/CD117, different subunits of the FcεRI receptor and proteins modulating metabolic processes. These findings suggest Siglec-6 has a broader role in regulating mast cell function and may contribute to the increased inhibitory effects observed with AK006 in vitro and in vivo. The publication is both available on the Allergy website as well as Allakos Scientific Presentations page. About AK006 AK006 is a humanized IgG1 monoclonal antibody which activates the inhibitory receptor Siglec-6. Siglec-6 is a member of the family of cell surface receptors called Sialic acid-binding immunoglobulin-type lectins (Siglecs). Siglec-6 is expressed primarily on the surface of mature mast cells. Siglec-6 receptors contain intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) which, when activated, recruit phosphatases that work to oppose activating signals driven by kinase signaling cascades. Because of this opposition to multiple activation pathways, AK006 has the potential to inhibit multiple modes of mast cell activation and has demonstrated preclinical inhibition of mast cell activation by IgE and through MRGPRX2 and KIT receptors. ITIM bearing receptors have important roles in regulating the immune system and therapeutics targeting ITIM bearing receptors, such as PD-1 and Siglec-10, have demonstrated therapeutic activity in immunology and oncology. AK006 appears to drive deep mast cell inhibition and, in addition to its inhibitory activity, can reduce mast cell numbers via antibody-dependent cellular phagocytosis (ADCP) in the presence of activated macrophages. AK006 is currently being tested in a Phase 1 study in healthy volunteers and will begin dosing in early 2Q 2024 in patients with chronic spontaneous urticaria. Results from the Phase 1 study are expected throughout 2024. About Allakos Allakos is a clinical stage biotechnology company developing therapeutics that target immunomodulatory receptors present on immune effector cells involved in allergy, inflammatory and proliferative diseases. Activating these immunomodulatory receptors allows for the direct targeting of cells involved in disease pathogenesis and, in the setting of allergy and inflammation, has the potential to result in broad inhibition of inflammatory cells. The Company’s most advanced antibody in ongoing clinical development is AK006. AK006 targets Siglec-6, an inhibitory receptor expressed on mast cells. Mast cells are widely distributed in the body and play a central role in the inflammatory response. Inappropriately activated mast cells have been identified as key drivers in a number of severe diseases affecting the gastrointestinal tract, eyes, skin, lungs and other organs. In preclinical studies, AK006 appears to provide deep mast cell inhibition and, in addition to its inhibitory activity, reduce mast cell numbers. For more information, please visit the Company’s website at www.allakos.com. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 as contained in Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Such forward-looking statements include, but are not limited to, Allakos’ progress, business plans, areas of focus and preclinical research; the potential of AK006; and Allakos’ anticipated milestones. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from current expectations and beliefs, including but not limited to: Allakos’ stages of clinical drug development; Allakos’ ability to timely initiate and complete clinical trials for AK006; Allakos’ ability to obtain required regulatory approvals for its clinical trials; uncertainties related to the enrollment of patients in its clinical trials; Allakos’ ability to demonstrate sufficient safety and efficacy of its product candidates in its clinical trials; uncertainties related to the success of clinical trials, regardless of the outcomes of preclinical testing or early-stage trials; Allakos’ ability to advance additional product candidates beyond AK006; uncertainties related to Allakos’ ability to realize the contemplated benefits of its restructuring and related reduction in force; Allakos’ ability to accurately forecast financial results; Allakos’ ability to obtain additional capital to finance its operations, research and drug development; general economic and market conditions, both domestic and international; domestic and international regulatory obligations; and other risks. Information regarding the foregoing and additional risks may be found in the section entitled “Risk Factors” in documents that Allakos files from time to time to with the SEC. These documents contain and identify important factors that could cause the actual results for Allakos to differ materially from those contained in Allakos’ forward-looking statements. Any forward-looking statements contained in this press release speak only as of the date hereof, and Allakos specifically disclaims any obligation to update any forward-looking statement, except as required by law. These forward-looking statements should not be relied upon as representing Allakos’ views as of any date subsequent to the date of this press release. Source: Allakos Inc. Investor Contact:Adam Tomasi, PresidentAlex Schwartz, VP Strategic Finance and Investor Relationsir@allakos.com Media Contact:Denise Powelldenise@redhousecomms.com

免疫疗法临床1期

2024-02-01

·佰傲谷BioValley

1月的裁员名单

2023年的裁员潮之后，2024也没个消停。2024年1月，已经有21家生物科技公司宣布进行裁员，不仅局限于小型生物技术公司，还包括了大型制药公司，例如拜耳、辉瑞。AlloVir裁员95%1月1日，AlloVir公司提交给美国证券交易委员会（SEC）的文件显示，AlloVir将现有的员工数量裁减约95%。截至2023年11月2日，该公司共有114名员工，裁员95%后，剩余的员工数量约为5~6个人。AlloVir裁员的主要原因是核心管线失败，为了降低成本和保护资产。2023年12月22日，由于核心管线posoleucel在3项III期研究中表现出“不太可能达到主要目标”的结果，AlloVir公司宣布终止全球3期研究，放弃对posoleucel的开发。张锋的Aera公司裁员25%Aera Therapeutics成立于2021年，由张锋、John Maraganore、Akin Akinc联合创立。在2023年筹集了1.93亿美元的A轮和B轮融资后正式公开亮相。1月4日，Aera公司宣布将进行裁员25%。根据报道，Aera公司裁员的主要原因是：鉴于当前生物技术的融资环境，采取措施节省资金，将资源集中在开发新型递送平台，并延长现金跑道。“CRISPR巨头”之一Intellia裁员1月4日，“CRISPR三大巨头”之一的Intellia公司发布未来三年战略重点，并宣布精简公司运营，裁员15%。Intellia公司报告，在内部战略审查之后，将精简公司运营，停止部分探索性研究阶段项目的工作（具体停止的项目未有披露），进一步将资源集中在关键的战略优先事项和计划上。因为早期项目的终止，Intellia公司将裁员15%。赛默飞关闭工厂1月4日，赛默飞世尔科技（Thermo Fisher Scientific）宣布，正在关闭位于加利福尼亚州佩塔卢马的工厂，并且裁员该工厂的74名员工。该工厂主要生产生产移液器吸头、微量离心管和支架等耗材。原因是该工厂的租约将于今年7月到期。Allogene裁员22%1月5日，Allogene Therapeutics终止核心产品cema-cel的两项临床研究，并将裁员22%。截至2023年2月，Allogene拥有361名员工。根据报道，Allogene公司将取消cema-cel的3线治疗研究ALPHA2和EXPAND的优先级，专注于推进cema-cel用于LBCL的一线（1L）巩固治疗的关键性2期试验ALPHA3。Senti裁员37%2024年1月5日，Senti Biosciences宣布公司将裁员37%。该消息发布在Senti首款候选药物的IND获得FDA批准之后。2023年12月，Senti公司在研CAR-NK细胞治疗SENTI-202已经获得美国FDA批准IND。Senti公司成立于2016年，由合成生物学大牛James J. Collins 和 Timothy Lu（卢冠达）等人所联合创立。尽管Senti公司有Timothy Lu等合成生物学大牛的背景加持，但是在资本寒冬中，一样面临着资金紧缺的挑战。这也是该公司裁员的主要原因。早先时候，该公司为了节省资金，已经停止了另一款管线的开发，并将其CMC工厂打包出售给Celadon Partners。延伸阅读：合成生物学大牛卢冠达的逻辑门CAR-NK获FDA批准INDAffimed裁员50%，首席执行官离职1月8日，德国生物技术公司Affimed宣布，为了延长现金流，公司将进行战略重组。通过重组计划公司的现金流将延长到2025年下半年。重组计划包括：Affimed将把所有资源用于推进其临床项目的发展；Affimed将通过解散其研究和临床前开发部门，将其员工人数减少多达50%；此外，该公司的首席执行官Adi Hoess博士也将离职。值得注意的是，今年早些时候（1月3日），Affimed将其全资子公司AbCheck出售给Ampersand Biomedicines。Affimed于2000年在德国成立，致力于发现和开发癌症免疫疗法的生物技术公司。公司重点关注先天细胞接合器（innate cell engager，ICE）领域，专注于开发靶向激活NK细胞的双抗药物。延伸阅读：裁员50%，首席执行官离职不缺钱，但裁员30%的C4 Therapeutics1月9日，C4 Therapeutics发布公告，宣布裁员约30%（45人）。与此同时，该公司将把重心放在两款自有药物（CFT7455、CFT1946）及一款合作药物（CFT8919）的临床研究上。虽然宣布裁员，但C4 Therapeutics并不拮据，裁员之举是为了重点推进现有的3款临床阶段的候选药物。目前公司拥有3.3亿美元的未经审计的现金、现金等价物和有价证券，预计现金流将延长至2027。Allakos核心管线失败，裁员50%2024年1月16日，Allakos宣布核心管线Siglec-8激动抗体lirentelimab在治疗特应性皮炎和慢性自发性荨麻疹的2项关键试验中，均未达到主要终点。因为lirentelimab的失败，Allakos公司同日宣布将进行公司重组，停止lirentelimab相关的临床、生产、研究和管理的工作，裁员50%；将重心转移至第二梯队的AK006和其他临床前管线的开发。同时，由于计划裁员50%和lirentelimab的收尾工作（包括遣散费以及其他）大约需要花费3000万美元。而截至2023年第四季度，该公司拥有约1.71亿美元的现金，预计能够支撑该公司运营至2026年年中。延伸阅读：心碎Biotech，彻底失败的核心管线Dewpoint两项合作失败，裁员15%1月16日，根据STAT新闻报道，Dewpoint Therapeutics裁员15%。主要原因是该公司与辉瑞和默克公司的两项合作的破裂。裁员之后将为新员工招募提供资金，专注于发展人工智能平台，并将首批药物推进临床。lonza关闭两个工厂1月17日，Lonza宣布关闭美国哈沃德工厂，裁减218个工作岗位。该工厂占地120,000平方英尺，专注于生物治疗药物、生物试剂和生物材料的临床生产。公司通告中将裁员背后的理由明确为工厂永久关闭。1月29日，Lonza宣布将进行裁员并关闭位于广州知识城的大分子工厂，该工厂主要提供大分子CDMO服务。据业内人士透露，该裁员举措的原因是由于“接不到订单”。然而，Lonza仍将在中国保留商业销售组织，以优化其全球网络和产能。拜耳裁减中层管理1月17日，德国制药巨头拜耳表示，公司已经和员工团体就削减大量工作岗位的计划达成一致，旨在减少层级、消除官僚主义、简化结构并加快决策流程。主要目的是减少公司内部的层级和复杂结构，因此裁员将包括承担管理或协调工作的员工。PMV裁员30%2024年1月18日，PMV Pharmaceuticals宣布将裁员30%。主要原因是，为了将现金流延长到2026年底。截止2023年12月3日，公司未经审计的现金、现金等价物和有价证券总额约为2.29亿美元。延伸阅读：精准肿瘤学公司，裁员30%被BMS分手后，Ikena裁员35%1月18日，Ikena Oncology宣布裁员35%（约20名员工），保留37名员工。该公司裁员的主要原因是，百时美施贵宝（BMS）终止了IK-412和IK-175两个项目的开发合作。由于BMS的放弃，Ikena公司也失去了潜在在9000万美元里程碑付款；在BMS退出后，Ikena公司也放弃了这两个项目的继续开发。延伸阅读：被BMS分手，放弃两条管线，裁员35%Cara首席科学官离职，裁员50%2024年1月22日，美国生物技术公司Cara Therapeutics宣布将裁员50%，并结束一项口服阿片类药物III期项目。与此同时，Cara首席科学官兼研发高级副总裁Frédérique Menzaghi博士将于2024年2月2日离开公司。这些措施能够大幅降低其运营费用，将公司的现金流延长到2026年。延伸阅读：首席科学官离职，裁员50%IND刚获批，Strand就裁员18%1月26日，根据Endpoints News报道，Strand Therapeutics已经裁员18%，被裁减的19名员工先前是参与早期项目工作的。裁员的原因，Strand公司首席执行官Jake Becraft表示：正在从平台转向管线开发，过去一两年内开发的一些工具，即使在研究中取得了成果，也不会用于药物产品当中。裁员发生在Strand的首款候选药物STX-001获得FDA批准IND后不到一周，STX-001于1月22日获得FDA的IND批准，STX-001是一款基于多机制合成的自复制mRNA疗法，由LNP递送瘤内给药，可直接进入肿瘤微环境并长时间表达IL-12细胞因子的肿瘤治疗候选药物。被罗氏分手后，Hookipa裁员30%1月29日，Hookipa宣布已经收到罗氏决定终止KRAS项目HB-700合作的通知；同时为了节省成本，Hookipa决定裁员约30%。但Hookipa并未放弃罗氏退回的HB-700，预计将于2024年第一季度提交IND；因为Hookipa仍有资格获得与提交IND申请相关的里程碑付款。目前，Hookipa公司将优先HB-200用于治疗HPV16+头颈癌的临床开发，以及于吉利德合作的传染病项目。此外，该公司不再进一步进行临床前项目开发（包括HB-300），以节约资金并确保优先管线的成功和公司运营。延伸阅读：被高瓴清仓，被罗氏退货Catamaran Bio暂停日常运营并裁员1月29日，根据Catamaran Bio的首席执行官Alvin Shih在LinkedIn上发布的帖子，Catamaran Bio将会停止日常运营，并为其CAR-NK细胞治疗候选物和技术寻找战略合作伙伴。截至周一早上，Catamaran有19名员工，其中“少数人”将留下来进行过渡期工作。Catamaran Bio成立于2020年，致力于开发同种异体CAR-NK细胞疗法，以治疗实体瘤；该公司尚未有推进临床的产品管线。辉瑞再裁52人，继续削减成本1月29日，Fierce Pharma报道称，辉瑞计划在旧金山南部的一家工厂裁员52人，继续削减成本。裁员将于2月中旬生效。该工厂地址与辉瑞于2022年以54以美元收购的Global Blood Therapeutics前总部相匹配。延伸阅读：辉瑞再实施5亿美元成本消减计划2seventy打包出售管线，裁员45%1月30日，2seventy bio宣布，除了已获批上市的Abecma外，将其余全部在研管线打包卖给再生元。再生元将向2seventy支付500万美元的预付款，以及首个交易管线获得市场批准后的一笔里程碑付款。除了在研管线之外，2seventyo的160名员工也跟随之被纳入再生元，包括其首席科学官Philip Gregory和首席医疗官Steve Bernstein。2seventyo的部分办公室、实验室和工厂也将归于再生元。出售所有在研管线后，2seventy将专注于Abecma的临床开发和商业化，且还将裁掉55名员工，约占剩余员工的45%。公司的首席执行官Nick Leschly已经离任，由首席运营官Chip Baird接任。延伸阅读：将仅靠BCMA-CAR-T活着的BiotechNovavax再裁12%1月31日，Novavax宣布将全球裁员12%（包括全职员工和承包商），这是作为Novavax转型的一部分努力。自从2023年Novavax启动公司转型，专注于在优先市场提供差异化的COVID-19疫苗以来，已经是第二次裁员了。根据新闻稿，Novavax一旦裁员完毕，预计员工人数将比2023年第一季度末减少30%。参考资料：1.https://www.biospace.com/article/biospace-layoff-tracker-2023-athenex-shutters-facility-cuts-staff/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········

高管变更临床申请临床3期临床2期基因疗法

2024-01-18

·佰傲谷BioValley

心碎Biotech，彻底失败的核心管线

2024年1月16日，Allakos宣布核心管线Siglec-8激动抗体lirentelimab在治疗特应性皮炎和慢性自发性荨麻疹的2项关键试验中，均未达到主要终点。继2021年lirentelimab宣布2项后期临床失败后，再次尝到失败滋味的Allakos，终于决定不再继续开发lirentelimab。因为lirentelimab的失败，Allakos公司同日宣布将进行公司重组，停止lirentelimab相关的临床、生产、研究和管理的工作，裁员50%；将重心转移至第二梯队的AK006和其他临床前管线的开发。该消息传出当日，截止收盘，Allakos公司股价大跌60.2%。和安慰剂没差的结果lirentelimab（AK002）是一款非岩藻糖基化的人源化IgG1单克隆抗体，可特异性激活抑制性受体Siglec-8，能够耗竭嗜酸性粒细胞并抑制肥大细胞的活化，从而治疗嗜酸性炎症疾病。体外和体内研究表明，lirentelimab可以抑制多种肥大细胞活化模式，包括IgE/FcεRI、 IL-33/STL2、Substance P/MRGPRX2和TLR3。人体临床研究中，lirentelimab显著减少血液和组织中的嗜酸性粒细胞。基于lirentelimab此前在临床前和早期临床的优异数据，以及lirentelimabz治疗嗜酸性胃炎/十二指肠和嗜酸性粒细胞性食管炎（EG/EoD）的失败，Allakos公司对lirentelimab在治疗荨麻疹和特异性皮炎上寄予厚望。除了传统的静脉注射制剂，Allakos公司还开发了lirentelimab的皮下制剂。在一项针对自发性荨麻疹的开放标签2a期试验中，接受lirentelimab每月6次治疗的患者7天荨麻疹活动评分(UAS7)改善75%，92%的患者荨麻疹控制测试(UCT)评分≥12。在EG/EoD 3期研究（ENIGMA 2）中，特应性皮炎合并症患者报告特应性皮炎疾病严重程度降低63%，而安慰剂组为12%。在另一项针对严重过敏性结膜炎的1b期研究中，特应性皮炎合并症患者报告疾病严重程度降低56% 。但遗憾的是，lirentelimab针对特应性皮炎患者的2期临床试验ATLAS和慢性自发性荨麻疹患者的2b期临床试验MAVERICK都失败了，两项评分EASI和UAS7与安慰剂组的相差无几，未能获得临床改善。尽管lirentelimab能够显著耗竭嗜酸性粒细胞，在组织学上实现了改善；在ATLAS研究当中，lirentelimab治疗组的嗜酸性粒细胞减少了96%，安慰剂组为15%；MAVERICK研究中，lirentelimab治疗组的嗜酸性粒细胞减少了95%，安慰剂组为5%。不过，这个结果也似乎早有预示。早在lirentelimab针对嗜酸性胃炎/十二指肠炎的III期ENIGMA 2研究和针对嗜酸性粒细胞性食管炎的II/III期研究KRYPTOS中，均表现出了组织学上的改善，但是未能够缓解症状负担。lirentelimab再次在荨麻疹和特异性皮炎上达到相同的结果，Allakos公司总算是决定彻底放弃lirentelimab。公司重组Allakos是一家临床阶段的生物技术公司，专注于开发靶向Siglec受体的治疗性抗体，特异性靶向肥大细胞和嗜酸性粒细胞，用于治疗过敏、炎症和增殖性疾病等疾病。靶向Siglec-8的lirentelimab是该公司最领先的管线，lirentelimab失败后，将重点开发靶向Siglec-6的AK006，Siglec-6功能与Siglec-8相似，但仅存在于肥大细胞上。AK006目前正在健康志愿者中进行I期研究，该公司的目标是在2024年第一季度完成其单剂量和多剂量递增队列。同时，由于停止了lirentelimab的开发，Allakos公司将计划裁员50%，预计lirentelimab的收尾工作（包括遣散费以及其他）大约需要花费3000万美元。而截至2023年第四季度，该公司拥有约1.71亿美元的现金，预计能够支撑该公司运营至2026年年中。小结组织学上有所改善，但是症状未能获得缓解——lirentelimab失败的很惨烈。Siglec-8的结局同时也给Siglec系列受体的开发蒙上一层阴影，Allakos公司其他的Siglec管线未来命运如何？延伸阅读：免疫检查点：Siglec家族分型、功能、临床进展参考资料：1.https://investor.allakos.com/news-releases/news-release-details/allakos-announces-restructuring-focus-development-ak0062.https://investor.allakos.com/news-releases/news-release-details/allakos-announces-phase-2-lirentelimab-trials-atopic-dermatitis3.https://www.allakos.com/science/#ak0074.https://investor.allakos.com/news-releases/news-release-details/allakos-announces-topline-phase-3-data-enigma-2-study-and-phase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2期临床结果临床终止临床失败