This is an open-label study of andecaliximab in participants at risk of developing bone where bone should not be, such as in muscle, tendons, and other soft tissues following traumatic spinal cord injury. The goal of this study is to assess the safety of andecaliximab, how much drug is in the body over time (pharmacokinetics/PK), and how it affects the body (pharmacodynamics/PD) in participants who have had a recent traumatic spinal cord injury.

开始日期2025-05-14

申办/合作机构

ashibio, Inc.

NCT06508021

/ Active, not recruiting临床2/3期

A Phase 2/3, Global, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Two-Part Study With Open-Label Extension (OLE) to Assess the Efficacy and Safety of Andecaliximab in Participants With Fibrodysplasia Ossificans Progressiva (FOP)

This study is researching an experimental drug called andecaliximab. The study will include pediatric and adult patients with fibrodysplasia ossificans progressiva (FOP). The study will evaluate how safe and effective andecaliximab is in patients with FOP.
The study is looking at several research questions, including:
* Safety of andecaliximab in participants with FOP
* Whether andecaliximab reduces the number of new heterotopic bone lesions (Heterotopic Ossification; HO)
* Whether andecaliximab reduces the number or severity of flare-ups
* Pharmacokinetics/pharmacodynamics (PK/PD): How much study drug is in your blood at different times and its impact on blood biomarker(s)
* Whether the body makes antibodies against the study drug (which could make the drug less effective or could lead to side effects)

开始日期2024-10-25

申办/合作机构

ashibio, Inc.

NCT02862574

/ Terminated临床2期

Evaluation of the Efficacy and Safety of GS-5745 as Add-On Therapy to a Tumor Necrosis Factor Inhibitor and Methotrexate Regimen in Subjects With Moderate to Severe Rheumatoid Arthritis

The primary objective of this study is to evaluate the efficacy of andecaliximab (GS-5745) versus placebo as an add-on therapy to a tumor necrosis factor (TNF) inhibitor and methotrexate in adults with moderate to severe rheumatoid arthritis (RA).

开始日期2016-12-15

申办/合作机构

Gilead Sciences, Inc.

100 项与 Andecaliximab 相关的临床结果

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100 项与 Andecaliximab 相关的转化医学

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100 项与 Andecaliximab 相关的专利（医药）

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项与 Andecaliximab 相关的文献（医药）

2025-09-01·PHARMACOTHERAPY

Biological Therapy and Small Molecules for Adults With Crohn's Disease: Systematic Review and Network Meta‐Analysis

Review

作者: Pontarolo, Roberto ; Gorski, Daniela ; Tonin, Fernanda Stumpf ; Lazo, Raul Edison Luna ; de Souza, Dalton de Assis ; Borba, Helena Hiemisch Lobo

ABSTRACT:

First‐line therapeutic approaches for Crohn's disease include immunosuppressants, aminosalicylates, and corticosteroids. However, more than one‐third of patients are resistant to these treatments and require second‐line therapies. Our goal was to synthesize the evidence on the efficacy and safety of biologics and small molecules for inducing remission in patients with moderate‐to‐severe Crohn's disease. A systematic review was conducted by searching for randomized controlled trials on the target population in PubMed, Scopus, and Web of Science (March 2025). Data synthesis for the outcomes of remission, health‐related quality of life (HRQoL), and safety was performed using network meta‐analyses and surface under the cumulative rating curve (SUCRA) analyses. The results were presented as risk ratios with 95% credible intervals. We included 55 trials ( n = 16,113 patients) evaluating 26 biological drugs across 83 doses and six small molecules across 15 doses. Similar results were obtained in the sensitivity analyses conducted across different measurement time points. Alongside infliximab 5 mg/kg (SUCRA 98.6%), 10 mg/kg (92%), and 20 mg/kg intravenous (91.8%), the recently approved drugs guselkumab 1200 mg (83.2%), 600 mg (89.2%), and 200 mg intravenous (90.1%), as well as mirikizumab 600 mg (91.5%) and 1000 mg intravenous (82.4%) presented higher probabilities of disease remission and were associated with increased HRQoL. Drugs such as certolizumab, andecaliximab, fontolizumab, abatacept, and etanercept ranked low for remission (SUCRA < 40%) and presented high probabilities of serious adverse events (over 60%). Small molecules presented an intermediate profile. Inhibitors of interleukin‐23 appear to be promising alternatives for the treatment of moderate‐to‐severe Crohn's disease. Given their safety profile, some anti‐TNF drugs should be avoided in practice. Trial Registration: PROSPERO: CRD42024519150

2025-06-04·Journal of Crohns & Colitis

Metabolism and response to stress gene signatures reveal ulcerative colitis heterogeneity and identify patients with increased response to therapy

Article

作者: Linggi, Bryan ; Vande Casteele, Niels ; Ma, Christopher ; Sangiorgi, Bruno ; Jairath, Vipul ; Smith, Michelle I ; Teft, Wendy ; Filice, Melissa

Abstract:

Background and Aims:

Ulcerative colitis (UC) therapies lead to variable remission and response rates in patients participating in clinical trials, likely due to interindividual target variability, differences in active biological pathways, feedback, and/or resistance mechanisms. Here, we stratified patients into subtypes by characterizing heterogeneity using mucosal biopsy transcriptomics data.

Methods:

Transcriptomics data from an andecaliximab phase 2/3 study in patients with UC were scored for gene signature enrichment. Eleven Reactome gene sets, moderately correlated with histological disease activity using Robarts Histopathology Index with low correlation to each other, were selected and evaluated in baseline gene expression data of ustekinumab, infliximab, and adalimumab clinical trials in patients with UC.

Results:

Of 11 gene sets, referred to as “Metabolism and Response to Stress” (MARS) signatures, 5 correlated with “non-disease” mucosa and 6 with “disease-related” mucosa. Clustering baseline andecaliximab samples scored with MARS revealed 3 clusters with low non-disease/high disease-related, high non-disease/low disease-related, or a mixture. Importantly, these clusters did not correlate with patient demographics, clinical characteristics, or disease activity metrics. Clustering baseline data from other clinical trials (anti-interleukin-12/23 and anti-tumor necrosis factor) in patients with UC scored with MARS showed that patients in low non-disease/high disease-related baseline score clusters less likely to achieve treatment response.

Conclusions:

We identified and evaluated a novel, multi-dimensional signature gene set to characterize previously undefined heterogeneity in patients with UC and identify patients less likely to respond to therapy. This approach offers potential utility to define clinical trial populations, enrich for clinical responders, and identify difficult-to-treat populations for therapeutic development.

2025-05-01·Cancer Medicine

Inside a Metastatic Fracture: Molecular Bases and New Potential Therapeutic Targets

Review

作者: Lorenzo Di Prinzio ; Alessandro Bruschi ; Elisa Bubbico ; Michele Fiore ; Massimiliano De Paolis ; Alberta Cappelli ; Andrea Pace ; Andrea Montanari ; Renato Zunarelli ; Cristina Scollo ; Andrea Sambri

ABSTRACT:

Introduction:

Bone metastases and pathological fractures significantly impact the prognosis and quality of life in cancer patients. However, clinical and radiological features alone have been shown to fail to predict skeletal related events of a bone metastasis (SREs).

Aim:

This study focuses on key molecular players including Matrix Metalloproteinases (MMPs), Integrins, Bone Morphogenetic Proteins (BMPs), Parathormone‐related Protein (PTHrP).

Results:

The RANK/RANKL/Osteoprotegerin (OPG) pathway, and N‐terminal peptide (NTx), involved in the metastatic process and bone integrity disruption. Elevated levels of these molecules have been pointed out as potential biomarkers for predicting SREs, but they have been poorly investigated. Moreover, batimastat, marimastat, tanomastat, andecaliximab, and HIV protease targeting MMPs; Volociximab/M200, cilengitide, abituzumab, and FAK inhibitors targeting integrins; LDN193189, DMH1, and ISLR modulators targeting BMPs; and PTH (7–33)‐CBD targeting PTHrP have shown promising results antagonizing these molecules, but no effect on preventing and managing metastatic fractures has been assessed yet.

Conclusions:

This paper underscores the importance of advanced molecular biology and transcriptomics in identifying novel therapeutic targets. The integration of these biomarkers with clinical and radiological assessments using artificial intelligence tools could revolutionize the diagnostics and treatment strategies for patients with bone metastases.

项与 Andecaliximab 相关的新闻（医药）

2025-10-23

·领康时代CDMO

【领康时代CDMO】IgG亚型选择指南：打造更安全有效的抗体药物

免疫球蛋白G（IgG）是人体血清中含量最丰富的抗体类型，约占血清免疫球蛋白总量的70%–85%，在适应性免疫应答中扮演着核心角色。IgG分子呈典型的Y形结构，由两条相同的重链（Heavy Chain）和两条相同的轻链（Light Chain）通过二硫键连接而成。重链和轻链的近氨基端的序列高度可变，称作可变区(V区，VH和 VL)；其余序列在遗传上较为稳定，称作恒定区(C区，CH和CL)。IgG抗体的重链恒定区可分为CH1、CH2和CH3三个结构域。其结构可进一步划分为抗原结合区域（Fab）和可结晶区域（Fc）：Fab区域负责特异性识别和结合抗原；而Fc区域则介导多种免疫效应功能，在Fc区域中存在一个高度保守的糖基化位点——Asn297，包括甘露糖、N-乙酰葡萄糖胺、半乳糖、唾液酸和岩藻糖等糖基。图1 IgG抗体的结构 IgG可进一步分为四个亚型：IgG1、IgG2、IgG3和IgG4，它们除了恒定区的CH2区不同，其它的恒定区序列高度同源。铰链区域在 Fab 末端与 Fc之间形成了一个灵活的连接体，这会影响 Fab 区域相对于 Fc 区域以及彼此之间的可能构象。各亚型在铰链区结构上也存在显著差异，包括二硫键的数量与位置：IgG1和IgG4含有2个铰链区二硫键，IgG2有4个，而IgG3则多达11个。此外，轻链与重链的连接位置也因亚型而异：IgG1连接于重链第5位半胱氨酸，而IgG2、IgG3和IgG4则连接于第3位。这些结构差异进一步影响了各亚类的糖基化模式、柔韧性及与受体的亲和力，从而导致它们在效应功能上的强弱不同。表1 IgG亚型的结构和功能差异 IgG抗体的四个亚型在免疫应答中表现出不同的特性。IgG1类抗体主要在对可溶性蛋白质抗原和膜蛋白抗原的应答中诱导产生，同时也可伴随较低水平的其他亚类抗体，尤其是IgG3和IgG4。针对细菌荚膜多糖抗原的免疫应答则主要诱发IgG2类抗体的生成。在效应功能方面，IgG3是一种强效的促炎抗体，能有效激活下游免疫效应机制，但其半衰期较短，这可能有助于防止过度的炎症反应。IgG4类抗体通常在非感染性、长期或反复暴露于抗原的情况下占主导地位，例如在慢性过敏或某些自身免疫环境中。抗体的效应功能是其最重要的生物学活性，目的在于灭活或清除传染源及其产物，IgG类抗体具有两种主要的效应功能：补体激活和Fcγ受体（FcγR）介导的调理和杀伤作用。特别值得注意的是，Fc区域中高度保守的糖基化位点Asn297引起的糖链结构对抗体与各类FcγR及补体蛋白C1q的结合具有决定性影响，进而调控如抗体依赖性细胞毒性（ADCC）、抗体依赖性细胞吞噬作用（ADCP）和补体依赖性细胞毒性（CDC）等重要免疫效应机制。图2 IgG与Fc效应分子的相互作用补体激活始于 C1q 的结合，在 CH2 区域中对于 C1q 结合起重要作用的残基包括 L235、D270、K322、P329 和 P331。在 IgG2 中，C1q 结合力的减弱似乎主要是由残基 A235（在其他亚类中为亮氨酸）引起的，而在 IgG4 中，P331在一定程度上是导致 C1q 结合减弱或缺失的原因。有研究表明，IgG3 的较长铰链使得 C1q 结合位点更加可及，从而导致补体激活更加有效。由于IgG2和 IgG4的铰链区比较短，仅有 12 个氨基酸残基，C1q 与 IgG2和IgG4 的结合可能会受到 Fab 区域对潜在结合位点的遮蔽作用的影响。综上所述IgG1 和 IgG3 能够有效触发这种经典的补体途径，但 IgG2 和 IgG4 的作用效率则要低得多。图3 IgG不同亚型重链恒定区序列图4 IgG不同亚型的结构 Fc区域与FcγR结合从而介导多种免疫反应，不同IgG亚型与不同的FcγR结合能力不同。FcγRI能与除 IgG2 以外的所有人类 IgG 亚类结合，IgG1和IgG3 与 FcγRI的结合能力高于IgG4 与 FcγRI的结合能力。在 IgG2 相同位置的 IgG1 的下铰链区域发生突变，特别是 E233P、L235A 和 G236突变，会破坏其结合能力；P331S 和 L234F 被认为是导致其与 IgG3 相比结合能力降低的原因。FcγRIIb/IIc与所有IgG亚型的结合能力都较弱，通常偏好为 IgG3=IgG1=IgG4> IgG2。 FcγRIII 通常与 IgG1 和 IgG3 结合，不与 IgG2 和 IgG4 结合，其中 IgG3 的结合效果优于 IgG1。因此 IgG1 和 IgG3 结合FcγR的能力强于IgG2 和 IgG4。新生儿Fc受体（FcRn）能与IgG的Fc区域结合，进而保护IgG免受降解，延长其在体内的半衰期。FcRn在生理 pH 值（7.4）下不会与其配体结合。只有在内吞小泡的酸性环境中（pH < 6.5），即 IgG 中暴露的组氨酸残基被质子化的情况下，才会发生与 FcRn 的结合。IgG 的 Fc 尾部（CH2-CH3 接口）内的组氨酸残基与 β2-微球蛋白（β2M）和 FcRn α 链的残基高亲和力结合至关重要。H435 位于该界面的核心位置，而含有 R435 的 IgG3 类型抗体与 FcRn 的亲和力降低，这解释了它们的半衰期缩短以及在胎盘中的转运量减少。目前市场上已有的治疗性抗体大多基于IgG框架构建，其中IgG1因具有较强的效应功能而成为主流选择，部分药物采用IgG2或IgG4亚型。IgG3虽然显示出更强的补体激活能力和细胞毒性，但由于其半衰期较短、存在较多异型多态性及潜在免疫原性，目前尚未被直接用于治疗性抗体开发。在实际药物设计过程中，根据治疗目标和机制的不同，需合理选择或改造IgG亚型： 1. 需要强效应功能的场景（如抗癌、抗感染药物） IgG1因其对FcγR和C1q的高亲和力，能有效介导ADCC、ADCP和CDC，成为该场景的首选。IgG3虽然效应功能更强，但因药代动力学性能较差，通常作为次要选项。此外，还可通过Fc区域点突变进一步增强其效应功能，例如S239D/I332E（DE）、G236A/S239D/I332E（GASDIE）等突变可增强与FcγR的结合；E345R/E430G等突变则能促进六聚体形成，显著增强补体激活能力。 2. 需要弱效应功能的场景（如抗炎、信号阻断类抗体） IgG2抗体亚型的效应功能相对较弱，这一特性使其成为治疗某些自身免疫病和感染性疾病的理想选择。IgG4与FcγR结合能力很弱，几乎不激活补体，非常适合用于需避免Fc介导的副作用（如非特异性细胞杀伤）的阻断型抗体。为彻底消除Fc区域的功能，还可引入L234A/L235A（LALA）、P329G（LALAPG）等突变降低与FcγR和C1q的结合，或通过N297A/Q去除糖基化，完全消除效应功能。 3. 需要延长半衰期的场景所有IgG亚型均可通过FcRn结合区工程化改造以延长其血清半衰期。常见策略包括引入M252Y/S254T/T256E（YTE）或M428L/N434S（LS）等点突变，增强其pH依赖性结合能力，从而减少溶酶体降解、增加循环时间。此外，IgG4还具有Fab臂交换（Fab-arm exchange, FAE）的能力，可在体内重组为功能上的单价双特异性抗体，为设计天然结构的双抗提供了独特途径。由于其较低的效应功能，IgG4被视为“非炎症性”亚型，更适合用于某些治疗场景。目前，基于IgG4框架的双特异性抗体已成为药物研发的热点。表2 临床研究阶段和已上市的基于IgG4亚型的治疗性抗体药物名称适应症靶点研发状态 IPH-2101 多发性骨髓瘤 KIR2D受体临床Ⅱ期 Inotuzumab ozogamicin 急性淋巴细胞白血病 CD22 批准上市 Reslizumab 哮喘 IL-5 批准上市 Lebrikizumab 哮喘 IL-13 批准上市 Ixekizumab 斑块状银屑病 IL-17 批准上市 GS-5745 胃癌或胃食管结腺癌 MMP9 临床Ⅱ/Ⅲ期 Tralokinumab 哮喘 IL-13 批准上市 Dupilumab 哮喘，特异反应性皮炎 IL-4α受体批准上市 Ibalizumab 艾滋病 CD4 批准上市 PRO-140, PA14 艾滋病 CCR5 临床Ⅱ期 LY2951742 习惯性的或复发性丛集性头痛 CGRP 批准上市综上所述，IgG亚型的选择与工程化改造是实现治疗抗体功能精准调控的关键策略。随着对抗体结构与功能关系理解的深入和蛋白质工程技术的发展，更多具有增强功能、延长半衰期、低免疫原性及双特异结合能力的抗体药物将被开发，广泛应用于肿瘤、自身免疫病、感染性疾病等多个治疗领域。参考文献吕若芸, 陈忱，魏敬双. "治疗性抗体药物开发中IgG亚型选择." 中国生物工程杂志 36.7(2016):8. Vidarsson, Gestur , G. Dekkers , and T. Rispens . "IgG Subclasses and Allotypes: From Structure to Effector Functions." Frontiers in Immunology 5(2014):520. Damelang，Timon , et al. "Impact of structural modifications of IgG antibodies on effector functions." Frontiers in Immunology 14.000(2023) :25. Natalia I. Majewska，Max L. Tejada，Michael J. Betenbaugh，Nitin Agarwal. "N-Glycosylation of IgG and IgG-Like Recombinant Therapeutic Proteins: Why Is It Important and How Can We Control It ?." Annual review of chemical and biomolecular engineering 11.1(2020). 关于领康时代领康时代重点打造国内外领先的生物制品CDMO技术服务平台，旨在为生物制品创新企业提供基于两大平台（哺乳动物细胞表达平台和微生物表达平台）的成药性评估、高质量的早期药理毒理研究样品生产、生产工艺开发、临床申报支持服务、临床样品生产和商业化生产的CDMO服务。领康时代郑重承诺公司将始终坚持：质量为先：严格执行国际GMP标准创新驱动：持续加大研发投入客户至上：不断提升服务质量我们诚挚期待与各界合作伙伴携手并进，共同推动生物医药产业高质量发展，为患者提供更多优质的治疗选择。联系领康电话 | 131 2081 8528 邮箱 | CDMO@lktime.cn 官网 | www.lktime.cn 官方微信公众号业务咨询微信

2025-08-20

·PipelineReview

āshibio Expands Clinical Pipeline with Vantictumab, a First-In-Class Antibody for Autosomal Dominant Osteopetrosis Type 2

– Company’s second clinical-stage asset licensed from Mereo Biopharma based on novel insights generated in a mouse model of osteopetrosis – – āshibio has exclusive license to develop and commercialize vantictumab globally, excluding Europe, where Mereo retains commercial rights – – Vantictumab development program is supported by safety and biomarker data generated in previous clinical trials – BURLINGAME, CA, USA I August 19, 2025 I āshibio , a privately held, clinical-stage biotechnology company developing novel therapeutics for the treatment of bone and connective tissue disorders, today announced an exclusive licensing agreement with Mereo BioPharma (NASDAQ: MREO) for vantictumab for the treatment of autosomal dominant osteopetrosis type 2 (ADO2), a rare, debilitating bone disorder with no approved therapies. The licensing of vantictumab represents a strategic expansion of āshibio’s pipeline of clinical-stage assets that address high unmet needs and carry significant clinical and commercial potential. ADO2, also known as Albers-Schönberg disease, is a genetic disorder caused by reduced function of osteoclasts. Impaired osteoclast function results in dense, brittle bone and leads to complications such as multiple fractures, poor bone healing, low blood counts (due to bone marrow sequestration), and painful nerve compression. The most common form of osteopetrosis, ADO2 results from a mutation in the chloride channel 7 (CLCN7) gene and has a reported incidence of 1 in 20,000 births. 1 “People living with autosomal dominant osteopetrosis type 2 face a lifetime of bone-related complications resulting in significant morbidity, multiple surgical procedures, chronic pain, and impaired quality of life – yet patients have no approved therapy to address the disease,” said āshibio Chief Executive Officer Pankaj Bhargava, MD. “Bringing vantictumab into our pipeline reflects our commitment to advancing therapies for rare skeletal conditions and improving the lives of those affected by serious bone disorders.” Vantictumab is a monoclonal antibody that selectively binds to certain frizzled (Fzd) receptors and inhibits Wnt signaling pathways. 2 Originally intended for the treatment of cancer, vantictumab has been previously evaluated in oncology clinical trials, demonstrating a favorable safety and pharmacokinetic profile. Previous clinical trials have provided biomarker data that directly support the activity of vantictumab on osteoclast function. These data significantly derisk the clinical program and allow āshibio to rapidly advance vantictumab into clinical development for ADO2. Preclinical data supporting the development of vantictumab in ADO2 will be presented at the upcoming American Society for Bone and Mineral Research (ASBMR) annual meeting, which takes place September 5-8, 2025 in Seattle, Wash. Under the terms of the agreement, āshibio will lead global clinical development for vantictumab in adult and pediatric patients. Mereo has granted āshibio an exclusive license to develop and commercialize vantictumab in the US and the rest of the world, excluding Europe, where Mereo retains commercial rights. About āshibio āshibio is a privately held, clinical-stage biotechnology company developing a pipeline of novel therapeutics for the treatment of bone disorders. Founded in 2022, āshibio exited stealth mode in June 2024 with $40 million in seed and Series A financing. The company has initiated a Phase 2/3 trial of its lead asset, andecaliximab, in patients with fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder characterized by progressive heterotopic ossification (HO), a pathological condition characterized by abnormal bone formation in muscle and soft tissues. āshibio has also initiated a development program in non-hereditary heterotopic ossification (NHHO), a severely disabling condition for which there are no approved therapies. The first study in the NHHO program is a Phase 1b trial of andecaliximab in patients with spinal cord injury at risk of HO. For more information, visit www.ashibio.com . About Mereo BioPharma Mereo BioPharma is a biopharmaceutical company focused on the development of innovative therapeutics for rare diseases. The Company has two rare disease product candidates: setrusumab for the treatment of osteogenesis imperfecta (OI); and alvelestat for the treatment of severe alpha-1 antitrypsin deficiency-associated lung disease (AATD-LD). Mereo’s partner, Ultragenyx Pharmaceutical, Inc., has completed enrollment in the Phase 3 portion of a pivotal Phase 2/3 study in pediatric patients and young adults (5 to 25 years old) for setrusumab in OI and in the Phase 3 study in pediatric patients (2 to <7 years old). The partnership with Ultragenyx includes potential additional milestone payments of up to $245 million and royalties to Mereo on commercial sales in Ultragenyx territories. Mereo has retained EU and UK commercial rights and will pay Ultragenyx royalties on commercial sales in those territories. Setrusumab has received Orphan Designation for osteogenesis imperfecta from the European Commission (“EC”) and the U.S. Food and Drug Administration (FDA), PRIME designation from the European Medicines Agency (EMA), and Breakthrough Therapy and Rare Pediatric Disease Designations from the FDA. Alvelestat has received Orphan Designation for AATD from the EC and the FDA, and Fast Track designation from the FDA for AATD-LD. Mereo has also entered into an exclusive global license agreement with ReproNovo SA, a reproductive medicine company, for the development and commercialization of leflutrozole, a non-steroidal aromatase inhibitor. In addition to the rare disease programs, Mereo has two oncology product candidates, etigilimab, an anti-TIGIT; and navicixizumab for the potential treatment of late-line ovarian cancer. Navicixizumab has been partnered with Feng Biosciences, Inc. in a global licensing agreement that includes milestone payments and royalties. For more information, visit www.mereobiopharma.com . 1 Wu CC, Econs MJ, DiMeglio LA, et al. Diagnosis and management of osteopetrosis: consensus guidelines from the Osteopetrosis Working Group. J Clin Endocrinol Metab . 2017 Sep 1;102(9):3111-3123. doi: 10.1210/jc.2017-01127 2 Diamond JR, Becerra C, Richards D, et al. Phase Ib clinical trial of the anti-frizzled antibody vantictumab (OMP-18R5) plus paclitaxel in patients with locally advanced or metastatic HER2-negative breast cancer. Breast Cancer Res Treat . 2020 Aug 14;184(1):53–62. doi: 10.1007/s10549-020-05817-w SOURCE: āshibio

引进/卖出孤儿药临床1期临床3期快速通道

2025-07-09

·小药说药

了解癌症中的金属蛋白酶

-01-引言金属蛋白酶（MP）是一个在其活性中心具有金属离子的大型蛋白酶家族。根据结构域的不同，金属蛋白酶可分为多种亚型，主要包括基质金属蛋白酶（MMPs）、解整合素金属蛋白酶（ADAMs）以及具有血栓反应蛋白基序的ADAMs（ADAMTS）。它们具有蛋白质水解、细胞粘附和细胞外基质重塑等多种功能。金属蛋白酶在多种类型的癌症中表达，并通过调节信号转导和肿瘤微环境参与涉及肿瘤发生、发展、侵袭和转移的许多病理过程。因此，更好地了解MP在癌症免疫调节中的表达模式和功能将有助于开发更有效的癌症诊断和免疫治疗方法。-02-一、MP的结构和表达基质金属蛋白酶（MMP）在脊椎动物中，MMP家族由28个成员组成，至少23个在人体组织中表达，其中14个在脉管系统中表达。基质金属蛋白酶通常根据其底物和其结构域的组织结构分为胶原酶（MMP1、MMP8、MMP13）、明胶酶（MMP2、MMP9）、溶血素（MMP3、MMP10、MMP11）、基质溶素（MMP7、MMP26）、膜型MMPs（MT MMPs）或其他MMPs。MMP家族有一个共同的核心结构。典型的MMPs由大约80个氨基酸的前肽、170个氨基酸的金属蛋白酶催化结构域、可变长度的连接肽或铰链区和约200个氨基酸的血红素蛋白结构域组成。不同类型的MMP具有不同于典型MMP的特定结构特征。例如，MT MMPs缺乏前结构域，而MMP7、MMP26和MMP23缺乏Hpx结构域和连接肽。此外，MMP2和MMP9包含纤连蛋白的三个重复。MMPs中的这些不同结构域、模块和基序参与与其他分子的相互作用，从而影响或决定MMP活性、底物特异性、细胞和组织定位。MMPs已在多种人类癌症中检测到，MMPs的高表达通常与大多数癌症的生存率降低有关，包括结直肠癌、肺癌、乳腺癌、卵巢癌和胃癌。其中MMP2和MMP9，能够降解基底膜中的IV型胶原，是研究最广泛的金属蛋白酶，与各种癌症患者的疾病进展和生存率降低相关。解整合素金属蛋白酶（ADAM）ADAMs是锚定在细胞表面膜上的I型跨膜蛋白，迄今已发现30多种。与MMPs类似，ADAMs包括前结构域和锌结合金属蛋白酶结构域。ADAM还包括一个在细胞表面蛋白中独特的去整合素结构域。ADAM的金属蛋白酶结构域高度保守，大多数ADAM都有一个富含半胱氨酸的结构域和跨膜区域相邻的EGF样结构域，然后是一个长度和序列在不同ADAM家族成员之间变化很大的胞内区。由于这些结构域的存在，ADAM可以结合底物并影响细胞粘附和迁移的变化，以及细胞表面分子的蛋白水解释放。它们的主要底物是完整的跨膜蛋白，如生长因子、粘附分子和细胞因子的前体形式。癌细胞通常表达高水平的ADAM，ADAM17是所有ADAM蛋白中研究最广泛的。一项评估ADAM17作为卵巢癌潜在血液生物标志物的研究表明，与对照组相比，培养的卵巢癌细胞系的培养基上清液以及卵巢癌患者的血清和腹水中的ADAM17水平明显更高。具有血栓反应蛋白基序的ADAM（ADAMTS）ADAM不同，ADAMTS是一种分泌型金属蛋白酶，其特征在于辅助结构域包含血栓反应蛋白1型重复序列（TSR）和间隔区，并且缺少跨膜区、胞内域和（EGF）样结构域，人ADAMTS家族包括19种蛋白。ADAMTS蛋白酶参与前胶原和von Willebrand因子的成熟，以及与形态发生、血管生成和癌症相关的ECM蛋白水解。研究表明，不同的ADAMTS具有不同的生物学功能，并且个体ADAMTS可以在不同的癌症中或根据临床环境发挥不同的作用。与MMPs和ADAMs相比，ADAMTS在TME中的参与研究较少，因此迫切需要系统地研究其在癌症中的功能。-03- 二、涉及癌细胞免疫相关MP的信号通路信号转导途径由多个分子组成，它们相互识别和相互作用，并传递信号以调节许多重要的生物学过程，如肿瘤细胞增殖、转移和免疫调节。三种信号通路尤其与免疫调节中的MP密切相关。肿瘤坏死因子信号肿瘤坏死因子-α（TNF-α）是一种重要的促炎细胞因子，参与免疫系统的维持和稳态，以及炎症和宿主防御。可溶性TNF-α通过蛋白水解酶ADAM17，也称为TNF-a转换酶（TACE），从跨膜TNF-α（tmTNF-α）裂解，该酶可通过激活TNF-α来协调免疫和炎症反应。鉴于ADAM17对TNF信号通路的受体和配体的作用，ADAM17被认为以多种方式影响TNF-α信号传导。例如，可溶性TNF-α产生的减少将导致tmTNF-α的积累，其将与TNFR2结合并导致不同的生物学结果。转化生长因子–β转化生长因子-β（TGF-β）作为肿瘤行为的关键调节因子，在肿瘤侵袭和转移、免疫调节和治疗抵抗中发挥重要作用。TGF-β也是TME免疫抑制的核心，根据具体情况对免疫系统具有多效性功能。MMP9和MMP2是已知的两种金属蛋白酶，可切割未激活的TGF-β前体并产生不同的TGF-β蛋白水解切割产物，从而导致TGF-β活化。此外，与CD44结合的MMP9降解纤连蛋白导致活性TGF-β的释放。癌细胞中MMP9的水平不仅可能影响TGF-β的蛋白水解，还可能影响TGFβ和TGF信号通路下游物质的表达。对乳腺癌中MMP9与TGF信号通路之间关系的研究表明，乳腺癌细胞中MMP9的过表达不仅显著上调了SMAD2、SMAD3和SMAD4的表达，还增强了SMAD2的磷酸化。Notch信号通路Notch信号涉及肿瘤生物学的多个方面，其在免疫应答的发展和调节中的作用比较复杂，包括塑造免疫系统和TME的组成部分，例如抗原呈递细胞、T细胞亚群和癌细胞之间的复杂串扰。特别是，Notch在不同免疫细胞的发育和维持中发挥着关键作用。配体与Notch受体结合后，下游信号由包括ADAM家族成员在内的一些蛋白酶介导。首先，受体/配体相互作用暴露了蛋白水解切割位点S2，其被ADAM金属蛋白酶切割。γ-分泌酶介导的S3处的后续裂解发生在跨膜区，导致Notch胞内结构域（NICD）的释放，该结构域转移到细胞核中，并将MAML与RBPJ结合，触发靶基因如Myc、P21和HES1的转录。已知ADAM10和ADAM17参与裂解S2，而ADAM17导致配体非依赖性Notch激活，ADAM10导致配体依赖性激活。-04-三、MP对肿瘤微环境的调节TME是指肿瘤细胞周围的微环境，包括血管、免疫细胞、成纤维细胞、骨髓源性抑制细胞、各种信号分子和ECM。TME在调节癌症的免疫反应中起着关键作用。MP对ECM的影响ECM是TME基质的非细胞成分，ECM的重塑在癌症的发展和体内稳态以及免疫细胞募集和组织转移中起着重要作用。癌症进展过程中ECM的广泛重塑导致其密度和组成发生变化，具体而言，蛋白酶诱导的ECM成分的分解对于肿瘤细胞跨越组织屏障至关重要。MMPs和ADAMs是参与ECM降解的主要酶，参与ECM降解的MMPs可大致分为膜锚定MMPs和可溶性MMPs。ECM降解主要通过MT1 MMP激活的可溶性MMP（如MMP2、MMP9和MMP13）实现。ECM有三个主要成分：纤维、蛋白聚糖和多糖。MMPs通过与这些基质结合以促进各种ECM蛋白的周转，在组织重塑中发挥重要作用。MMPs降解ECM的具体机制尚不清楚，需要进一步研究。MP与免疫细胞之间的关系MP在促进免疫细胞活性和调节免疫细胞迁移方面发挥重要作用。MP和免疫细胞之间的关系如下图所示。ADAM10和ADAM17在静止的CD4+Th细胞表面表达，对调节CD4+Th的发育和功能很重要。ADAM10/17在T细胞共刺激受体以及共抑制受体的脱落中发挥关键作用。例如，CD154（CD40L）是一种II型膜共刺激受体，在T细胞和APC之间的相互作用后，CD154表达在几个小时内迅速上调，随后在ADAM10和ADAM17裂解后从T细胞表面释放。此外，ADAM10和ADAM17还作用于共刺激受体CD137，以及抑制性受体LAG-3、TIM-3，sLAG-3和sTIM-3的可溶性形式都是在ADAM10和ADAM17蛋白水解裂解后形成的。B细胞是体液免疫的关键细胞成分，位于脾脏中边缘区B细胞（MZB）表达高水平的CD80/86共刺激分子，导致T细胞活化。Notch2信号传导是MZB细胞发育所必需的，在MZB的发育过程中，Notch2异二聚体与基质细胞和APC上的DLL1等配体结合，这启动了一种未知的金属蛋白酶水解受体，导致Notch胞内结构域的释放，该结构域转移到细胞核并触发下游靶基因的表达。这种未知的金属蛋白酶可能是ADAM10。NK细胞表达IgG Fc受体FcγRIII（CD16），CD16分子可被ADAM17从活化的NK细胞表面裂解，ADAM17的抑制会削弱CD16和CD62L的胞外脱落，从而显著增加细胞内TNF-α和IFN-γ的水平。此外，MMPs和ADAMS可以从肿瘤细胞表面切割活化受体NKG2D的配体。这些裂解蛋白的可溶性形式与NKG2D结合，并诱导该受体的内吞和降解，导致肿瘤逃避监控。总的来说，ADAM17裂解的多种底物与NK细胞的不同作用有关。肿瘤相关巨噬细胞（TAM）有助于癌症的发生和恶性进展，高水平的TAM与预后不良和总体生存率降低有关。在多种癌症中，发现TAM通过分泌MMPs促进肿瘤血管生成和侵袭，并调节免疫反应。MMP的调节与TAM分泌的趋化因子密切相关。与MPs相关的免疫调节细胞因子多种来源于肿瘤细胞的细胞因子，包括TGF-β、EGF、HGF和TNF-α，介导许多MP的表达。其中最重要的是MMP9，其在血清和与肿瘤相关的组织中升高，并参与ECM的降解，以促进癌症中免疫细胞的迁移。此外，这些细胞因子必须被MP切割以参与肿瘤免疫过程。例如，被ADAM17切割的TmTNF-α产生活性sTNF-α。IL-12在T细胞发育和扩增中也起着关键作用，未激活的IL-12前体需要在被MMP14切割之后在TME中转变为活性状态。金属蛋白酶和血管生成迄今为止，已经报道了几种类型的肿瘤血管生成，包括萌芽血管生成和血管生成拟态（VM）。萌芽血管生成是通过血管基底膜中各种水解酶（如MP和组织纤溶酶）的上调实现的，这导致基底膜和ECM的降解和重塑。例如，在胰腺神经内分泌肿瘤中，MMP9分泌增加会从基质中释放出隔离的VEGF，从而将血管静止转变为活跃的血管生成。在肺癌细胞中，MMP2活性的抑制减少了其与整合素AVB3的相互作用，并抑制了下游PI3K/AKT信号介导的VEGF的表达，导致血管生成减少。VM是侵袭性肿瘤形成新血管的新模型，为肿瘤生长提供血液供应。研究表明，实体瘤的初始缺氧环境与VM密不可分，缺氧与MMPs的表达和活性密切相关。低氧诱导因子-1α（HIF-1α）已被证明直接调节MMP14、MMP9和MMP2的表达。-05-四、靶向MP的免疫治疗鉴于MP在癌症免疫调节中的作用，人们开始探索靶向MP的免疫治疗，临床试验中出现了多种广谱MP抑制剂。然而，由于药物的非特异性靶向和MP在免疫调节中的复杂作用，MP抑制剂迄今未能改善癌症患者的生存和预后。最近，有报道称MP抑制剂可用于联合治疗，以提高免疫治疗的疗效。SB-3CT作为一种MMP2/9抑制剂，被认为可以提高抗PD-1和抗CTLA-4治疗黑色素瘤和肺癌小鼠模型的疗效。SB-3CT治疗不仅通过减少多种致癌途径导致PD-L1表达减少，而且与抗PD-1治疗相结合，显著改善了免疫细胞浸润和T细胞的细胞毒性。此外，SB-3CT与抗CTLA-4的组合增强了PD-L1表达的下调，并增加了肿瘤中活化的肿瘤浸润CD8+T细胞的丰度。Andecaliximab（GS-5745）是一种选择性抑制MMP9的单克隆抗体，GS-5745通过与MMP9前体结合并阻止MMP9活化来抑制MMP9，而与活性MMP9的结合则抑制其活性。Fab 3369作用于MMP14，阻断细胞表面表达的内源性MMP14，并抑制三阴性乳腺癌（TNBC）中ECM的降解。此外，有多种抗体可有效抑制ADAM17，包括A12、A9和MED13622。还有一些小分子抑制剂在临床开发中，在临床试验中显示出积极的效果。-06-结语MP在TME中的免疫调节中发挥重要作用，包括ECM重塑、信号通路转导、细胞因子脱落和释放以及促进血管生成。与MP相关的新兴技术和药物在癌症诊断和治疗中得到了越来越多的探索。因此，更好地了解MP在癌症免疫调节中的表达模式和功能将有助于开发更有效的癌症诊断和免疫治疗方法。基于MP的探索和新技术具有巨大潜力，它们可能会为未来的癌症诊断和治疗提供有效的策略。参考资料：1.Quantifying antibody binding: techniques and therapeutic implications. MAbs. 2025 Feb 16;17(1):2459795欢迎加入我的知识星球，可免费下载每次直播的原始文献和PPT，小药邀请你到知识星球一起学习！公众号已建立“小药说药专业交流群”微信行业交流群以及读者交流群，扫描下方小编二维码加入，入行业群请主动告知姓名、工作单位和职务。

免疫疗法

100 项与 Andecaliximab 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11262	Andecaliximab	-	DB12296

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
骨化性肌炎	临床3期	美国	ashibio, Inc.	2024-10-25
胃食管交界处腺癌	临床3期	美国	Gilead Sciences, Inc.	2015-10-13
胃食管交界处腺癌	临床3期	澳大利亚	Gilead Sciences, Inc.	2015-10-13
胃食管交界处腺癌	临床3期	比利时	Gilead Sciences, Inc.	2015-10-13
胃食管交界处腺癌	临床3期	智利	Gilead Sciences, Inc.	2015-10-13
胃食管交界处腺癌	临床3期	哥伦比亚	Gilead Sciences, Inc.	2015-10-13
胃食管交界处腺癌	临床3期	捷克	Gilead Sciences, Inc.	2015-10-13
胃食管交界处腺癌	临床3期	法国	Gilead Sciences, Inc.	2015-10-13
胃食管交界处腺癌	临床3期	德国	Gilead Sciences, Inc.	2015-10-13
胃食管交界处腺癌	临床3期	匈牙利	Gilead Sciences, Inc.	2015-10-13

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02862535 (Pubmed) 人工标引	临床1期	胃腺癌一线	16	S-1+cisplatin+andecaliximab	網醖遞鹽網範糧繭餘膚(觸鹽構壓範壓鹽鏇積鑰) = Peripheral sensory neuropathy (69%), anorexia (63%), nausea (56%), and decreased neutrophil counts (44%) were the most common adverse events (AEs). 齋襯齋築顧廠廠網廠艱 (築觸願構築觸遞窪齋膚 ) 更多	积极	2022-06-30
				S-1+oxaliplatin+andecaliximab
DDW2022	N/A	克罗恩病	-	Infliximab	齋鹹鏇繭簾積夢遞鹹鑰(獵簾繭廠醖衊齋襯觸壓) = no significant differences were observed between placebo, comparators or any biologic 築壓範膚觸獵廠製廠鑰 (構齋廠衊獵糧網膚膚網 ) 更多	-	2022-05-22
				Adalimumab
NCT02862535 (Pubmed \| J Immunother Cancer)	临床1期	胃食管交界处腺癌	36	Andecaliximab monotherapy	夢壓鹽醖顧積選襯艱遞(窪鹽簾淵艱築膚獵齋鹽) = PK of andecaliximab in Japanese patients with gastric or GEJ adenocarcinoma was similar to that reported in non-Japanese patients with advanced solid tumors 製衊選膚顧糧鑰淵衊願 (鏇願廠齋廠遞餘鹽廠廠 ) 更多	积极	2022-01-01
				Andecaliximab + Nivolumab
NCT02864381 (GS-US-296--2013, Pubmed \| J Immunother Cancer)	临床2期	晚期胃癌	144	Andecaliximab plus Nivolumab	網鬱憲齋願鑰蓋醖獵憲(鹹鏇顧醖願鏇鬱窪繭鏇) = 選醖築築積網膚鏇顧範夢鏇醖築壓壓壓簾繭選 (餘製襯蓋艱鹽願艱齋淵, 4 ~ 19)	不佳	2021-12-01
				Nivolumab alone	網鬱憲齋願鑰蓋醖獵憲(鹹鏇顧醖願鏇鬱窪繭鏇) = 夢鏇製構繭蓋廠夢築齋夢鏇醖築壓壓壓簾繭選 (餘製襯蓋艱鹽願艱齋淵, 2 ~ 16)
NCT02545504 (GAMMA-1, Pubmed) 人工标引	临床3期	胃食管交界处腺癌一线 EGFR2 negative	432	Andecaliximab+fluorouracil	鏇觸蓋鬱膚觸鹽鹹膚廠(膚範製艱糧鏇壓壓觸獵) = 獵選艱淵窪構艱艱鏇積築蓋餘蓋遞網齋齋選鏇 (鏇憲鹹遞衊製積膚醖憲 ) 更多	不佳	2021-03-20
				Placebo+fluorouracil	鏇觸蓋鬱膚觸鹽鹹膚廠(膚範製艱糧鏇壓壓觸獵) = 壓築鏇窪蓋夢網網廠選築蓋餘蓋遞網齋齋選鏇 (鏇憲鹹遞衊製積膚醖憲 ) 更多
NCT02862535 (###DELETE \| phase 1b \| NCT02862535, CTgov)	临床1期	进展期胃腺癌 \| 复发性胃食管结合部腺癌 \| 胃腺癌 ... 更多	36	Andecaliximab (Cohort 1: ADX)	膚選憲襯構製鹽觸獵網 = 願蓋鹹鹹淵製醖鹹艱窪襯積鬱積構積範鏇艱醖 (糧顧獵願鑰鹽艱鹹構鏇, 齋膚蓋糧選艱築繭觸鬱 ~ 艱糧衊簾壓憲願膚構繭) 更多	-	2020-12-24
				Andecaliximab+S-1+cisplatin (Cohort 2: ADX + S-1 + Cisplatin)	膚選憲襯構製鹽觸獵網 = 築構範糧鏇膚淵餘獵鏇襯積鬱積構積範鏇艱醖 (糧顧獵願鑰鹽艱鹹構鏇, 淵淵獵網衊遞糧衊鏇範 ~ 遞築壓憲窪築壓製夢鹹) 更多
NCT02864381 (GS-US-296--2013, CTgov)	临床2期	复发性胃食管结合部腺癌 \| 胃腺癌 \| 胃食管交界处腺癌	144	Nivolumab+Andecaliximab (Andecaliximab + Nivolumab)	壓遞製觸鑰衊鏇網製觸(鹽築醖鹹積憲觸憲遞製) = 遞獵蓋淵鏇餘壓膚夢淵鏇鏇窪構鹽艱繭壓餘鹽 (觸窪範鬱襯襯簾鏇遞夢, 鹽繭願願衊簾築顧築襯 ~ 鹽簾襯廠壓築鑰鏇選膚) 更多	-	2020-09-18
				Nivolumab (Nivolumab)	壓遞製觸鑰衊鏇網製觸(鹽築醖鹹積憲觸憲遞製) = 選簾壓壓蓋膚鑰願遞憲鏇鏇窪構鹽艱繭壓餘鹽 (觸窪範鬱襯襯簾鏇遞夢, 鬱鏇襯齋鑰遞網築選鏇 ~ 蓋襯窪夢窪夢廠網膚構) 更多
NCT02077465 (CTgov)	临床1期	慢性阻塞性肺疾病	11	Andecaliximab	艱積遞艱餘蓋夢鏇顧製 = 鏇繭鹹餘夢繭齋襯憲遞淵鑰醖餘鹹膚淵範壓鏇 (糧築夢網獵獵壓壓築願, 衊鑰獵鏇鹹築醖齋網艱 ~ 艱艱構壓願獵選醖鹹襯) 更多	-	2020-08-13
NCT02545504 (GAMMA-1, CTgov)	临床3期	胃腺癌 \| 胃食管交界处腺癌	432	mFOLFOX6+Andecaliximab (Andecaliximab + mFOLFOX6)	築願襯廠廠衊窪餘製鬱(鹽餘觸蓋鹹鹹憲獵壓壓) = 夢鏇遞積網膚簾遞壓衊憲廠鑰襯膚淵顧願網鑰 (蓋膚壓遞積鬱選鬱鑰願, 鏇淵簾廠鏇積範壓願夢 ~ 築壓艱淵遞艱衊餘餘選) 更多	-	2020-04-28
				mFOLFOX6 (Placebo + mFOLFOX6)	築願襯廠廠衊窪餘製鬱(鹽餘觸蓋鹹鹹憲獵壓壓) = 鑰餘壓構鹹築範衊繭願憲廠鑰襯膚淵顧願網鑰 (蓋膚壓遞積鬱選鬱鑰願, 鑰積齋餘餘淵鑰獵餘鑰 ~ 膚遞範餘範鬱壓膚製築) 更多
NCT02862535 (ASCO_GI2019)	临床1期	晚期胃食管交界处腺癌	16	Andecaliximab 800 mg + S-1+cisplatin	襯衊壓壓廠願鑰蓋選鏇(襯製衊齋觸艱獵淵艱範) = 艱窪繭鬱簾鬱憲齋選範願網網範構憲繭窪鑰顧 (願簾網築夢醖憲鏇憲簾 )	积极	2019-01-29