Multiple myeloma (MM) is a plasma cell disease characterized by the growth of clonal plasma cells in the bone marrow. The purpose of this study is to assess the adverse events and change in disease activity of etentamig in combination with a cereblon E3 ligase modulatory drug (CELMoD) agent in adult participants with relapsed/refractory (R/R) multiple myeloma (MM). Adverse events and change in disease state will be assessed.
Etentamig is an investigational drug being developed for the treatment of R/R MM. Study doctors put the participants in groups called treatment arms. Multiple doses of etentamig in combination with iberdomide will be explored. Each treatment arm receives a different dose of etentamig and iberdomide to determine a tolerable dose. Approximately 135 adult participants with R/R MM will be enrolled in the study in approximately 50 sites worldwide.
In phase 1 participants will receive escalating intravenous (IV) etentamig in combination with oral iberdomide. In phase 2 participants will receive IV etentamig at one of two doses in combination with oral iberdomide, as part of the approximately 129 month study duration.
There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at an approved institution (hospital or clinic). The effect of the treatment will be frequently checked by medical assessments, blood tests, questionnaires and and monitoring of side effects.

开始日期2025-06-30

申办/合作机构

TeneoOne, Inc.

NCT06348108

/ Not yet recruiting临床1期IIT

A Phase Ib, Multi-center, Study of Talquetamab in Combination With Iberdomide and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma

This phase I trial will evaluate the safety, side effects, and best dose of talquetamab in combination with iberdomide and dexamethasone in treating patients with multiple myeloma that has come back after a period of improvement (relapsed) or has not responded to previous treatment (refractory). There is currently a significant unmet need for patients with relapsed or refractory multiple myeloma (RRMM) who are triple class refractory and have been exposed to B-cell maturation antibody (BCMA) targeted therapy. These patients currently have limited treatment options and poor survival. Talquetamab is an FDA approved drug that can bring T-cells to the myeloma cell, resulting in myeloma cell death. Iberdomide is an investigational drug and works by targeting and destroying proteins that help myeloma cancer cells to survive. Dexamethasone is a corticosteroid, is similar to a natural hormone produced by the adrenal glands to reduce inflammation (swelling, heat, redness, and pain) and is used to in helping to treat certain types of cancer including myeloma.

开始日期2025-05-01

申办/合作机构

The University of California, San Francisco

[+2]

NCT06232044

/ Suspended临床1/2期IIT

A Phase I/II Study of the Safety, Tolerability and Efficacy of Belantamab Mafodotin (GSK2857916) in Combination With Iberdomide (CC-220)/Dexamethasone Versus Belantamab Mafodotin (GSK2857916)/Dexamethasone in Relapsed Refractory Multiple Myeloma

This phase I/II trial tests the safety, side effects, best dose, and effectiveness of iberdomide in combination with belantamab mafodotin and dexamethasone in treating patients with multiple myeloma (MM) that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). Multiple myeloma is a cancer that affects white blood cells called plasma cells, which are made in the bone marrow and are part of the immune system. Multiple myeloma cells have a protein on their surface called B-cell maturation antigen (BCMA) that allows the cancer cells to survive and grow. Immunotherapy with iberdomide, may induce changes in body's immune system and may interfere with the ability of cancer cells to grow and spread. Belantamab mafodotin has been designed to attach to the BCMA protein, which may cause the myeloma cell to become damaged and die. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Iberdomide plus belantamab mafodotin may help slow or stop the growth of cancer in patients with multiple myeloma.

开始日期2025-04-23

申办/合作机构

Alliance for Clinical Trials in Oncology

[+1]

100 项与伊伯多胺相关的临床结果

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100 项与伊伯多胺相关的转化医学

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100 项与伊伯多胺相关的专利（医药）

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项与伊伯多胺相关的文献（医药）

2025-06-02·CANCER RESEARCH

Targeted Degradation of Mutant p53 Reverses the Pro-oncogenic Dominant-Negative Effect

Article

作者: Gencel-Augusto, Jovanka ; Lozano, Guillermina

p53 is a transcription factor that functions as a tumor suppressor and the active unit of which is a tetramer. Nearly all cancers inactivate the p53 pathway, primarily through missense mutations in TP53. Most mutant p53 proteins lose their function and often exhibit increased protein stability. In addition to this loss of function, mutant p53 can drive oncogenicity through a dominant-negative effect by forming mixed tetramers with wild-type (WT) p53 to inhibit its activity. The study in this issue of Cancer Research by Klemm and colleagues provides definitive evidence for the mechanism by which mutant p53 inactivates WT p53 function. The p53R248Q mutant has a longer half-life than WT p53, resulting in an approximate ratio of 3 or 4 mutant molecules to every WT molecule. This imbalance facilitates the dominant-negative effect, which can be overcome either by exogenously increasing WT p53 levels or by selectively degrading mutant p53. In experiments whereby mutant p53 was degraded using a degron-tagged construct combined with iberdomide as a molecular glue, remarkable therapeutic efficacy was observed when this approach was used in combination with an MDM2 inhibitor. This work paves the way for therapeutic strategies that aim to degrade mutant p53 proteins in cases in which a WT TP53 allele is retained.See related article by Klemm et al., p. 1978

2025-06-01·ANNALS OF THE RHEUMATIC DISEASES

Responsiveness of systemic lupus erythematosus subjects to iberdomide based on molecular endotypes

Article

作者: Bachali, Prathyusha ; Lipsky, Peter E ; Daamen, Andrea ; Korish, Shimon ; Grammer, Amrie ; Schafer, Peter ; Hu, Yanhua

OBJECTIVES:

Iberdomide is a cereblon E3-ligase modulator that promotes proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) and was shown to be efficacious among subjects with generalised systemic lupus erythematosus (SLE). This study sought to identify baseline gene expression profiles of SLE subjects responsive to iberdomide and analyse the impact of this agent on gene expression.

METHODS:

Whole blood samples obtained from 276 female SLE subjects in the phase 2b iberdomide trial (NCT03161483) were assessed by RNA sequencing followed by gene set variation analysis (GSVA) using 32 informative gene modules. Unsupervised K-means clustering categorised subjects according to molecular endotypes at baseline. Each endotype was compared for treatment related gene expression changes.

RESULTS:

K-means clustering of GSVA scores from whole blood yielded 5 patient subsets (endotypes A-E) with increases in molecular abnormalities indicative of enhanced immune activity. Significant clinical responses to iberdomide, determined using the SLE Responder Index 4, were confined to endotypes C and E. The most important treatment related gene modules in responders in endotype E were Treg cells, B cells, and interferon, whereas unfolded proteins, oxidative phosphorylation and anergic/activated T cells were associated with responsiveness in endotype C.

CONCLUSIONS:

Molecular profiles of SLE subjects identified pharmacodynamic effects of iberdomide that occurred in all endotypes as well as changes in specific gene modules altered in endotypes associated with a significant clinical response. Thus, gene expression-based molecular profiling may be useful to enrich clinical trials for treatment-responsive subjects and also monitor the pharmacodynamic impact of therapy.

2025-05-16·ACS Chemical Biology

Exploring the Potential of Homologous Recombination Protein PALB2 in Synthetic Lethal Combinations

Article

作者: Keller, Aramis ; Gillingham, Dennis ; Zhanybekova, Saule ; Sauter, Basilius ; Lu, Xinyan

Cells with defective homologous recombination (HR) are highly sensitive to poly(ADP-ribose) polymerase (PARP) inhibition. Current therapeutic approaches leverage this vulnerability by using PARP inhibitors in cells with genetically compromised HR. However, if HR factors in cancer cells could be inhibited or degraded pharmacologically, it might reveal other opportunities for synergistic combinations. In this study, we developed a model system that recapitulates PARP/HR synthetic lethality by integrating a small-molecule responsive zinc-finger degron into the HR factor Partner and Localizer of BRCA2 (PALB2). We further tested a series of peptide ligands for PALB2 based on its natural binding partners, which led to the discovery of a high affinity peptide that will support future work on PALB2 and HR. Together, our findings validate PALB2 as a promising drug target and provide the tools and starting points for developing molecules with therapeutic applications.

项与伊伯多胺相关的新闻（医药）

2025-06-13

·药明康德

近100%癌症患者达缓解！百时美施贵宝靶向蛋白降解组合疗法亮眼结果公布

百时美施贵宝（Bristol Myers Squibb）日前在欧洲血液学协会（EHA）年会上，展示了其靶向蛋白降解平台的最新研究数据，包含该公司在研的口服E3泛素连接酶cereblon调节剂（CELMoD）药物mezigdomide（MEZI）和iberdomide（IBER）在多发性骨髓瘤（MM）患者中的更新临床研究结果，以及golcadomide（GOLCA）在非霍奇金淋巴瘤（NHL）中的研究进展。此外，该公司也公布其潜在“first-in-class”的口服BCL6配体导向降解剂（LDD）BMS-986458在NHL中的初步研究结果。值得关注的是，研究数据显示，golcadomide联合利妥昔单抗治疗复发/难治性滤泡性淋巴瘤（R/R FL）患者展现出显著疗效，总缓解率（ORR）高达94%，完全缓解率（CR）为63%，为临床治疗带来新的希望。蛋白降解剂如CELMoD药物和LDD，旨在靶向并降解导致疾病的特定蛋白，包括许多传统小分子抑制剂难以靶向的蛋白。这些创新疗法有望增强现有治疗效果，克服多种恶性疾病中的耐药性，从而改善患者预后。以下为百时美施贵宝在EHA年会期间展示的靶向蛋白降解研究要点：Mezigdomide百时美施贵宝公布了MM-002研究中mezigdomide联合地塞米松及硼替佐米（A组，n=28）和联合地塞米松及卡非佐米（C组，n=27）在复发/难治性多发性骨髓瘤（RRMM）患者中的剂量递增阶段数据。分析显示，A组的ORR为75.0%，C组为85.2%。A组和C组的中位缓解持续时间（DOR）分别为10.9个月（95% CI：8.8–18.7）和11.9个月（95% CI：6.4–35.9）。A组和C组的中位无进展生存期（PFS）分别为12.3个月和13.5个月。此外，研究扩展阶段D组（n=49）在既往接受过1–3种治疗的RRMM患者中的分析结果显示，该患者群体的ORR为85.7%，中位DOR为19.4个月（95% CI：9.7–不可评估），中位PFS为17.5个月。安全性方面，最常见的3/4级治疗伴发不良事件（TEAE）为中性粒细胞减少症，通过使用药物和调整剂量进行管理。图片来源：123RF而mezigdomide联合其他口服创新药物形成三联方案在RRMM患者中的分析数据则显示：Mezigdomide+EZH2抑制剂tazemetostat+地塞米松组合的ORR为50%（n=16）。Mezigdomide+BET抑制剂BMS-986158+地塞米松组合的ORR为35%（n=20）。Mezigdomide+MEK抑制剂trametinib+地塞米松组合的ORR为80%（n=20）。此外，分析显示，上述组合可激活并扩增NK和T细胞，包括既往接受过T细胞重定向疗法的患者。安全性方面，最常见的3/4级TEAE为中性粒细胞减少，非血液学3/4级TEAE较少。IberdomideMM-001研究更新结果显示，iberdomide联合硼替佐米和地塞米松（IberVd）在不适合移植的新确诊多发性骨髓瘤（NDMM）患者中表现出持久且深入的缓解。在中位随访25个月时，意向治疗人群（n=18）的ORR为88.9%，其中66.6%达到CR或更好。此外，44%的CR患者达到最小残留病（MRD）阴性。安全性方面，最常见的3/4级血液学TEAE为中性粒细胞减少（29.4%）；2例（11.8%）出现3/4级外周神经病。总体最常见的3/4级TEAE为感染（47.1%）。Golcadomide评估golcadomide单药或联合利妥昔单抗治疗R/R FL的研究数据更新结果指出，在A部分（剂量递增阶段）中，golcadomide单药治疗患者的ORR为67%，CR率为42%。在B部分（扩展阶段）中，0.4 mg golcadomide联合利妥昔单抗治疗的患者ORR为94%，CR率为63%；中位DOR为4.8个月，中位随访时间为5.75个月。在既往接受来那度胺或T细胞重定向治疗的患者中亦观察到一致反应。安全性方面，B部分（n=60）中最常见的3/4级治疗相关不良事件为中性粒细胞减少（60%）和贫血（13%），未见因不良反应停药，非血液学不良事件较少且多为低等级。而评估golcadomide单药或联合利妥昔单抗治疗复发/难治性弥漫大B细胞淋巴瘤（R/R DLBCL）的研究结果则显示，使用0.4 mg golcadomide联合利妥昔单抗治疗的患者中，ORR为58%，CR率为44%，中位DOR为14.5个月。而在接受过T细胞重定向疗法的患者中，ORR为56%，CR率为38%。在全部患者（n=77）中最常见的3/4级治疗相关不良事件为中性粒细胞减少（64%）和贫血（20%）。大多数不良事件可控，停药率为7%。根据早期研究结果，mezigdomide、iberdomide和golcadomide正在多个3期研究中进行评估。BMS-986458这次百时美施贵宝也公布了BMS-986458在复发/难治性非霍奇金淋巴瘤患者中的人体初步研究结果。这是一项开放标签、多中心、剂量递增研究，共纳入31例重度经治患者。分析显示，在外周血和肿瘤组织中均观察到BCL6的快速且持久的降解。从最低剂量起即观察到在DLBCL和FL患者中的抗肿瘤活性。在21名可评估疗效的患者中，ORR为81%（N=17），CR率为23.8%（N=5）。此外，BMS-986458的耐受性良好，最常见治疗相关不良事件为1/2级关节痛（19.4%）和疲劳（16.1%）；未观察到≥3级的细胞减少或因不良反应停药。这些积极结果支持该药物的进一步开发。参考资料：[1] Bristol Myers Squibb Presents Data Across Targeted Protein Degradation Research Including CELMoD™ Agents and BCL6 Ligand-Directed Degrader at EHA 2025. Retrieved June 13, 2025 from https://news.bms.com/news/details/2025/Bristol-Myers-Squibb-Presents-Data-Across-Targeted-Protein-Degradation-Research-Including-CELMoD-Agents-and-BCL6-Ligand-Directed-Degrader-at-EHA-2025/default.aspx免责声明：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。版权说明：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「药明康德」微信公众号回复“转载”，获取转载须知。👇 分享，点赞，在看，聚焦全球生物医药健康创新

临床结果临床研究细胞疗法

2025-06-12

·PipelineReview

Bristol Myers Squibb Presents Data Across Targeted Protein Degradation Research Including CELMoD™ Agents and BCL6 Ligand-Directed Degrader at EHA 2025

Innovative Agents Highlight Growth of Targeted Protein Degradation Platform and BMS’ Leadership in Innovative Cancer Therapies PRINCETON, NJ, USA I June 12, 2025 I Bristol Myers Squibb (NYSE: BMY) today announced the presentation of new data from its targeted protein degradation platform during the 2025 European Hematology Association (EHA) Annual Congress being held from June 12-15 in Milan, Italy. Presentations feature updated clinical findings on the company’s investigational oral CELMoD™ agents mezigdomide and iberdomide in multiple myeloma, and golcadomide in non-Hodgkin lymphoma, as well as the first results evaluating the company’s first-in-class, oral BCL6 ligand-directed degrader (LDD) (BMS-986458) in non-Hodgkin lymphoma. The latest data presented for the three lead CELMoD agents and BCL6 LDD underscore the potential impact that these therapies may have in addressing significant unmet medical needs in hematologic malignancies. These agents are part of continuing research across targeted protein degradation at Bristol Myers Squibb, which also encompasses additional CELMoD agents, LDDs and degrader antibody conjugates (DACs) across blood cancers and solid tumors, as well as non-malignant hematologic disorders. Protein degraders, like CELMoD agents and LDDs, are therapies designed to target and degrade specific proteins that drive diseases, including many proteins that are difficult to target through conventional small-molecule inhibitors. These innovative agents have the possibility to enhance the efficacy of existing therapies and overcome resistance in various malignancies, potentially improving patient outcomes. “As a leader in the field of targeted protein degradation, we are committed to applying our decades of expertise to the development of these next wave of agents. The efficacy and safety data presented at the EHA Annual Meeting this year is promising and reinforces the potential of CELMoD agents in combination with other standard treatments,” said Anne Kerber, Senior Vice President, Head of Development, Hematology, Oncology and Cell Therapy for Bristol Myers Squibb. “These analyses also add to the body of evidence for these programs as we continue pivotal studies for each of the agents that we anticipate reading out in the next year and onwards.” Key targeted protein degradation data being presented by Bristol Myers Squibb at the EHA Annual Congress include: Mezigdomide (MEZI): Abstract #4160130 : Updated results were presented from the dose-escalation phase of the MM-002 study for the combinations of mezigdomide, dexamethasone, and bortezomib (Cohort A MeziVd; n=28), and mezigdomide, dexamethasone, and carfilzomib (Cohort C MeziKd; n=27) in patients with relapsed/refractory multiple myeloma (RRMM) who had received 2–4 prior therapies: Results from the dose-expansion cohort (Cohort D) of the study were also presented for the MeziVd combination (n=49) in patients with RRMM who had received 1–3 prior therapies: The most common grade 3/4 treatment-emergent adverse event (TEAE) across arms was neutropenia and was managed with G-CSF and dose modifications. Abstract #4160802 : New data was presented evaluating mezigdomide in all-oral triplet combinations with other oral novel agents in RRMM. Iberdomide (IBER): Abstract #4160144 : Updated results were presented from MM-001, evaluating the combination of iberdomide, bortezomib, and dexamethasone (IberVd) in patients with transplant-ineligible, newly diagnosed multiple myeloma (NDMM), confirming durable, deep responses in the study. Golcadomide (GOLCA): Abstract #4160953 : Updated results were presented from a study evaluating golcadomide with or without rituximab for the treatment of R/R follicular lymphoma (FL). Patients with R/R FL who had received ≥2 prior lines of treatment received golcadomide monotherapy in the dose-escalation part of the study (Part A), followed by golcadomide once daily at 0.2 or 0.4 mg with or without rituximab in the expansion part (Part B). Results continued to show promising efficacy with durable responses in heavily pre-treated patients with R/R FL. Abstract #4161005 : Updated results were presented from a study evaluating golcadomide with or without rituximab for the treatment of R/R diffuse large b-cell lymphoma (DLBCL). Patients received golcadomide once daily at either 0.2 mg (n=39) or 0.4 mg (n=38). Results continued to show durable responses in heavily pre-treated patients with R/R DLBCL and a consistent safety profile. Based on the results of early studies, mezigdomide, iberdomide and golcadomide are being evaluated in multiple phase 3 studies: BMS-986458 BCL6 LDD: Abstract #4160340: First clinical findings were presented from the dose-escalation part of the first-in-human, multicenter, open-label study of BMS-986458 in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Initial results evaluating 31 heavily pre-treated patients treated with BMS-986458 were promising and support continued development for the treatment of NHL. Bristol Myers Squibb: Creating a Better Future for People with Cancer Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine and, through innovative digital platforms, are turning data into insights that sharpen their focus. Deep understanding of causal human biology, cutting-edge capabilities and differentiated research platforms uniquely position the company to approach cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future. About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn , X , YouTube , Facebook and Instagram . SOURCE: Bristol Myers Squibb

临床结果临床3期

2025-06-11

·精准药物

最新进展！分子胶合理设计的时代来了

作者｜小麦最近，分子胶（Molecular Glue）领域又迎来一波小高潮。先是在5月20日，Blueprint Medicines修订了与VantAI的协议，达成了潜在高达16.7亿美元的交易。Blueprint 被VantAI最近推出的基础模型Neo-1所吸引，Neo-1模型有助于加快新型诱导邻近疗法的发现和开发，实现了基于人工智能（AI）的分子胶和其他PPI修饰化合物的生成。旋即在第二天，即5月21日，罗氏与Orionis Biosciences达成了第二次合作，追加20亿美元共同开发针对肿瘤领域创新和具有挑战性靶点的小分子单价分子胶药物。Orionis的AlloGlues分子胶平台，融合了先进的化学生物学工具、工程化细胞检测系统、定制高通量机器人自动化技术以及专用AI基础架构，从而可以加速分子胶的发现和合理设计。借助人工智能（AI）和大数据，分子胶的合理开发变得越来越有可能。 01 分子胶从“偶然发现”到“合理设计”分子胶是一类小分子，可改变蛋白质的表面特性以增强或诱导蛋白质-蛋白质相互作用（PPI），从而导致特定的生物效应，如蛋白质降解、通路抑制或激活。分子胶的独特特性赋予它们高选择性和生物利用度，允许控制药物释放。分子胶在治疗糖尿病、心血管疾病、眼科疾病和癌症等疾病方面显示出巨大的临床潜力。分子胶最成熟的应用是诱导靶向蛋白质降解（TPD）。通过在靶蛋白和E3 连接酶之间诱导PPI，产生由“靶蛋白-分子胶-E3 连接酶”组成的三元复合物。这种三元复合物的形成诱导靶蛋白的多泛素化，导致其通过泛素-蛋白酶体途径降解，这类分子胶称为分子胶降解剂。与传统疗法相比，TPD方法的主要优势在于它能够靶向更广泛的靶点，尤其是“不可成药”的靶点。PROTAC（蛋白水解靶向嵌合体）和分子胶是TPD分子的两大类。与 PROTAC相比，分子胶在几个方面具有优势。例如，分子胶具有更好的物理化学性质、较低的亲和力要求以及减少或没有钩状效应（图1）。这些优异的特性使分子胶成为药物开发的更好候选者[1]。图1. PROTAC和分子胶比较然而，分子胶的发现比PROTAC更具挑战性，分子胶降解剂的发现主要依赖于各种筛选策略，通常涉及偶然发现、高通量筛选或药物化学指导的理性设计。分子胶的作用机制（MoA）涉及诱导蛋白质-蛋白质相互作用，这通常伴随着构象变化。因此，分子胶的早期发现过程通常具有较低的命中率。这也使构效关系（SAR）分析和基于结构的药物设计复杂化。此外，分子胶命中对化学修饰高度敏感。鉴于这些挑战，大规模筛查仍然是分子胶发现的主流方法。不过，随着各类分子胶发现平台的出现，以及人工智能（AI）在药物研发上的应用，分子胶的研发正在从“碰运气”走向系统开发，这也使得分子胶再次成为药物研发的风口，正逐步成为制药巨头们争相布局的重点领域。据不完全统计，近两年，分子胶领域已产生十几笔交易，总金额超过130亿美元，这一数据足以证明其市场潜力。 02 分子胶平台全球多家公司拥有独特的分子胶发现平台，包括Orionis Biosciences的Allo-Glue™平台，Magnet Biomedicine的TrueGlue平台和药明生物分子胶发现平台等。2.1 Orionis Biosciences的Allo-Glue™平台AlloGlues分子胶平台通过重编程蛋白质功能并通过近端或远端变构机制影响疾病靶点（包括曾经被认为“不可成药”的靶点）来诱导或增强特定的蛋白质-蛋白质相互作用。AlloGlues分子胶平台用系统、大规模的发现、设计和优化各种单价胶取代了二元和偶然发现，该平台集成了多种技术，能够在多个维度上研究分子相互作用的复杂性（图2），包括：a. 实验和计算机数据采集的规模和速度：通过将专有生物分析与定制自动化、机器人技术、专业数值建模和OrionisBio™ AI/ML工具相结合，大规模发现和分析活细胞中的蛋白质-蛋白质相互作用；b.发现模式：大规模启用以靶标为中心、反向靶标中心和连接酶为中心的方法；c.化学多样性：他们的化合物库中的骨架多样性有助于探索大型化学空间；d.专用 Orionis SAR-Enhancer AI：专有工具，支持对包含超过1万亿个分子的虚拟但易于合成的化合物空间进行多变量计算机模拟查询，从而推动快速的 SAR和胶水优化周期；e.蛋白质多样性：支持跨~20,000种蛋白质（基因组规模）和数百种合格连接酶的询问范式，以评估活细胞中胶反应性蛋白质的相互作用。图2. AlloGlues分子胶平台2.2 Magnet Biomedicine的TrueGlue平台TrueGlue平台是一种模块化的技术，能够系统地发现用于治疗人类疾病的分子胶。它通过高通量筛选和优化，快速识别能够诱导蛋白质相互作用的分子胶候选物，从而为药物发现提供新的靶点和机制。当TrueGlue与呈现蛋白结合时，会产生一个neo-PPI界面，介导与疾病靶蛋白形成三元复合物，并导致靶蛋白连接酶依赖性结合。TrueGlues平台具有以下优点：a.新型PPI可以克服靶蛋白配体性的局限性；b.呈现蛋白的组织特异性可以最大限度地减少脱靶毒性；c.细胞外呈现蛋白可以使细胞因子/受体的胶抑制剂用口服小分子代替可注射生物制剂（图3）。图3. TrueGlue分子胶平台2.3 药明生物分子胶发现平台药明生物开发了一个全面的分子胶发现平台，配备了DNA编码文库（DEL）、亲和选择质谱（ASMS）和高通量筛选（HTS）技术（图4）。图4. 药明生物分子胶发现平台药明生物提供两种类型的通用小分子DEL，用于分子胶的发现。一个是多元化的库，包含200多个由不同合成路线构建的子库，拥有超过500亿个结构。这些化合物是根据来自公共信息的6,000多个生物活性骨架设计的，包括已批准或处于临床阶段的药物、公共数据库、专利或文献。这些不同的文库非常适合没有报道的分子胶或配体的靶标（图5）。图5. 用于分子胶发现的DEL筛选平台另一种是以分子胶为重点的文库，基于已报道的小分子配体或分子胶的核心骨架设计。该文库通过广泛的化学修饰显著扩展了核心骨架的化学空间，同时保持了较高的靶标特异性和成功率。药明生物开发了一种靶向CRBN的免疫调节酰亚胺药物（IMiD）重点文库。CRBN分子胶的溶剂暴露区域对于底物识别和诱导PPI至关重要。通过应用不同的合成路线和构建单元，对溶剂可及界面进行了广泛的修改。这生成了一个包含大约600万种溶液和磁珠上化合物的集中文库。对于具有现有分子胶和配体的靶标，聚焦文库方法可以确保良好的筛选性能和命中率（图6）。图6. DEL在药明生物分子胶发现中的应用2.4 Monte Rosa Therapeutics的QuEEN平台QuEEN平台首先构建了一个包含超过10,000种结构的专有化学库，这些结构专门用于泛素连接酶的重编程。这些化合物经过精心设计，能够与E3泛素连接酶（如CRBN）相互作用，从而诱导目标蛋白的降解（图7）。QuEEN平台整合了人工智能（AI）技术，构建了预测模型，用于预测分子胶降解剂的活性和选择性。这些模型能够加速药物发现过程，减少实验成本和时间。QuEEN‌平台主要有三个模块：1）CRBN配体衍生分子库，2）接近性筛选技术和化学-蛋白质组学验证，3）AI预测模型[2]。图7. QuEEN分子胶平台为构建CRBN靶点图谱，Monte Rosa通过计算挖掘人类蛋白质组中类似已知CRBN新底物β-hairpin G-loops的基序（Degron结构）来筛选neo-substrate（图8）。图8. Monte Rosa利用Degron结构筛选neo-substrate2.5 Proxygen的分子胶平台Proxygen的分子胶平台是一个高度通用且可扩展的发现引擎，专注于识别和开发分子胶降解剂。该平台具有高度通用性、整合了尖端基因组学、蛋白质组学和生化技术以及目标导向等特点（图9）。图9. Proxygen的分子胶平台2.6 达歌生物的GlueXplorer平台GlueXplorer是由达歌生物开发的全球领先的分子胶药物发现平台，GlueXplorer平台拥有超过10,000种具有独特结构的分子胶化合物，这些化合物及其诱导邻近和降解靶点蛋白的数据构成了一个强大的化合物库。这一丰富的化合物库为新靶点的发现和分子胶的优化提供了坚实的物质基础（图10）。GlueXplorer平台利用人工智能技术，能够精准预测新型可降解靶点，该平台专注于开发针对以往难以成药靶点的新型分子胶降解剂药物。图10. 达歌生物的GlueXplorer平台 03 在研的分子胶降解剂截至目前，全球共有3款分子胶药物获批上市，包括沙利度胺（Thalidomide）、来那度胺（Lenalidomide）和泊马度胺（Pomalidomide）（图11）[3]。图11. 获批上市的分子胶药物除上述获批药物之外，还有很多在研的分子胶药物，如Mezigdomide、Golcadomide、Iberdomide和BMS-986470等（图12）。图12. 部分在研的分子胶降解剂 04 代表性药物4.1 BMS-986470胎儿血红蛋白（HbF，α2γ2）的再激活是公认的镰状细胞病（SCD）疾病调节剂，其中治疗有限且仍然存在大量未满足的需求。已经确定了几种HbF的转录抑制因子，包括B细胞淋巴瘤/白血病11A（BCL11A）、锌指和含有BTB结构域7A（ZBTB7A）和广泛间隔的锌指蛋白（WIZ）[4]。BMS-986470是由BMS开发的一种潜在的首创口服生物可利用的HbF激活CRBN E3连接酶调节剂（CELMoD™）试剂，靶向ZBTB7A和WIZ进行降解来诱导胎儿血红蛋白（HbF）的表达，从而改善镰状细胞病（SCD）的病理。临床前动物药效显示：在人红细胞生成的小鼠模型中，BMS-986470不影响人成红细胞分化，并显示出hZBTB7A和hWIZ蛋白的显著剂量依赖性降低，以及F细胞和γ-珠蛋白表达的增加。值得注意的是，与载体对照相比，以最小有效剂量治疗的小鼠的总HbF水平增加了3倍。BMS-986470 还显着诱导表达人CRBN的Townes小鼠外周血中的F细胞和γ-珠蛋白，并在缺氧条件下减少离体镰状细胞。在每天用BMS-986470治疗16天的幼稚健康食蟹猴中，观察期为2周，WIZ和ZBTB7A的显着剂量依赖性降解很明显，同时循环未成熟红细胞增加，HBG1/2转录本，外周血和骨髓中γ-珠蛋白和红系祖细胞标志物增加。BMS-986470在所有测试剂量下均具有良好的耐受性。BMS-986470正在进行1/2期临床试验（NCT06481306），旨在评估其在健康志愿者和镰状细胞病（Sickle Cell Disease, SCD）患者中的安全性、耐受性、药代动力学（PK）、药效学（PD）和初步疗效。该试验计划招募184名受试者，预计主要完成日期为2027年1月6日。4.2 KPG-818和KPG-121康朴生物是一家于2011年1月成立的创新型生物医药企业，专注于自身免疫疾病、癌症、炎症等治疗领域，以国际领先的分子胶-蛋白质泛素化降解技术NeoMIDES®和gDACs®、X-SYNERGY®等自主专利技术为基础，致力于开发具有全球自主知识产权的创新药物，主要研发管线包括KPG-818和KPG-121等（图13）。图13. 康朴生物研发管线KPG-818是由康朴生物开发的一种靶向IKZF1/IKZF3新型口服分子胶免疫调节药物，通过与CRBN蛋白结合，高效降解IKZF1和IKZF1，用于治疗系统性红斑狼疮（SLE）、血液肿瘤和炎症性肠病（IBD）等。KPG-818 在多种血癌动物模型中表现出出色的体外抗炎特性、广泛的抗增殖活性和显着的体内疗效。去年6月，KPG-818的一项2a期研究（NCT04643067）取得积极结果：0.15mg KPG-818组的SLEDAI评分和皮肤红斑狼疮疾病面积和严重程度指数（CLASI）活性评分相对于基线和安慰剂有所改善（图14）[5]。KPG-818 显示出良好的剂量暴露相关性和10小时的半衰期；KPG-818减少了总B细胞、Aiolos T细胞和Aiolos B细胞的数量，并增加了Treg细胞。图14. KPG-818的临床2a期试验结果总得来说，KPG-818 0.15 mg和0.6 mg在该SLE人群中12周的治疗中总体耐受性良好。概念验证结果表明，KPG-818是一种具有新型免疫调节作用机制的药物，在SLE中具有良好的获益/风险比，支持KPG-818在SLE中的进一步临床开发。2025年4月，康朴生物宣布CDE已批准KPG-818胶囊用于治疗SLE的中度至重度皮肤表现的IIb期临床试验（CTR20241116）。同时，KPG-818 目前正在美国（NCT04283097）进行用于治疗血液系统恶性肿瘤患者的 I/II 期研究。KPG-121是一种新型小分子靶向蛋白降解药物，属于新一代CRBN E3泛素连接酶复合物CRL4CRBN调节剂，它通过靶向CK1α和转录因子Aiolos及Ikaros的泛素化和降解，具有抑制细胞增殖活性和抗血管生成活性，同时增强免疫调节功能。与来那度胺相比，KPG-121与CRBN的相互作用更强，免疫调节活性更强，抗增殖/抗血管生成特性更强。KPG-121 在临床前研究中与阿比特龙、恩扎卢胺、阿帕他胺或达罗他胺联合使用体外和体内都显示出协同作用。2024年ASCO会议上，评估KPG-121 联合阿比特龙、恩扎卢胺或阿帕他胺在 mCRPC 患者中的安全性、PK和初步疗效的首次人体 1 期研究结果被公布。研究结果显示：在8例RECIST可评估疾病患者中，3例（37.5%）部分缓解，3例（37.5%）疾病稳定。总体而言，客观缓解率和疾病控制率分别为37.5% （3/8例）和75.0%（6/8例）。KPG-121的PK评估表明，半衰期范围为2.66至 2.83小时[6]。2023年11月，康朴生物医药宣布将启动KPG-121治疗转移性去势抵抗性前列腺癌的全球多中心II/III期注册性临床试验。2025年1月，KPG-121联合阿比特龙用于一线治疗转移性去势抵抗性前列腺癌的2/3期临床试验申请已获得美国FDA批准。4.3 ICP-490ICP-490是由诺诚健华研发的靶向IKZF1/3的高效选择性的降解剂，通过特异性结合CRL4CRBN-E3泛素连接酶复合体，诱导转录因子IKZF1和IKZF3的泛素化和降解。2023 年 9 月， ICP-490 联合地塞米松的临床试验获批开展。ICP-490 作为单一疗法或与其他疗法联合治疗在血液肿瘤治疗中显示出强大的潜力。ICP-490在与单抗药物的联合治疗中表现出免疫调节活性。低剂量的ICP-490可强力诱导IL-2和颗粒酶B的释放，有效提升抗CD38单抗药物在多发性骨髓瘤中的疗效。在非霍奇金淋巴瘤中，ICP-490与BTK抑制剂奥布替尼联合使用时展现出协同抑瘤作用。ICP-490目前正在进行的2期临床试验包括，包括ICP-CL-01102（NCT06845241）和ICP-CL-01101（NCT05719701）。ICP-CL-01102是一项多中心、非随机和开放标签的 I/IIa 期临床研究，以评估 ICP-490 在复发或难治性非霍奇金淋巴瘤患者中的安全性、耐受性和有效性，预计主要完成日期为2028年7月1日。ICP-CL-01101是一项多中心、非随机和开放标签的 I/IIa 期临床研究，旨在评估 ICP-490 在复发和/或难治性多发性骨髓瘤患者中的安全性、耐受性和有效性，预计主要完成日期为2025年7月30日。4.4 GLB-001和GLB-002格博生物是一家于2020年12月成立的专注于分子胶靶向蛋白降解药物研发的生物医药公司，公司已建立了多维度蛋白降解筛选平台、创新靶点验证平台、分子胶理性设计平台，以及专有高活性分子库，主要产品管线包括GLB-001和GLB-002等（图15）。图15. 格博生物的研发管线GLB-001是由格博生物研发的一款靶向酪蛋白激酶1α（CK1α）的分子胶蛋白降解剂，于2024年2月获得NMPA批准在髓系恶性肿瘤中开展临床研究，是国内首款进入临床开发阶段的靶向CK1α分子胶蛋白降解剂。2023年4月，GLB-001已获得FDA批准进入临床研究，用于复发/难治性急性髓系白血病（R/R AML）或复发/难治性较高危骨髓异常增生综合征（R/R HR-MDS）的治疗（GLB-001-01，NCT06146257）。GLB-001-01是一项首次人体（FIH）、1 期、开放标签、剂量递增和扩展临床研究。该研究的剂量递增部分（1a期）将评估口服GLB-001的安全性、耐受性、PK、PD和初步疗效。大约24名参与者（最多42名参与者）可以参加该研究的1a期。将遵循剂量扩展部分（1b期）以了解剂量、暴露、毒性、耐受性和临床活性之间的关系，确定最低活性剂量，并为2期研究选择推荐剂量。最多24名参与者（每个剂量水平12名参与者）可以参加该研究的1b阶段。GLB-002是由格博生物研发的一款靶向IKZF1/3的分子胶蛋白降解剂，于2023年10月7日获得NMPA批准在非霍奇金淋巴瘤（NHL）及多发性骨髓瘤（MM）等血液肿瘤中开展临床试验（GLB-002-01，NCT06219356）。小结分子胶是一类备受关注的小分子药物类型，获批上市的分子胶药物中来那度胺销售额2021年全球销售额达到峰值128.9亿美元，2005-2023年累计销售额高达近900亿美元。这一巨大市场吸引国内外药企纷纷布局，分子胶井喷期即将到来。参考文献1.Molecular Glues Discovery & Development - WuXi Biology2.Monte Rosa Therapeutics: Mining the CRBN Target Space Redefines Rules of Neo-substrate Engagement3.Molecular Glues Approved Drugs And Pipeline Analysis4.169 Development of a ZBTB7A and Wiz Dual Degrading, HbF-Activating CELMoD™ for the Treatment of Sickle Cell Disease5.POS0057KPG-818, A NOVEL CEREBLON MODULATOR IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS: RESULTS OF A RANDOMIZE, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 2A STUDY6.KPG-121, a novel cereblon modulator, in patients with metastatic castration resistant prostate cancer: Results of a phase I multiple ascending dose study.声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

蛋白降解靶向嵌合体引进/卖出

100 项与伊伯多胺相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11134	-	-	DB12101

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
多发性骨髓瘤	临床3期	美国	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	日本	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	澳大利亚	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	奥地利	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	比利时	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	巴西	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	加拿大	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	捷克	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	丹麦	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	芬兰	Alcami Corp.	2022-06-23

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临床结果

适应症

分期

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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


NCT05199311 (phase 1/2 study, ASCO2025)	临床2期	多发性骨髓瘤	38	Carfilzomib, iberdomide, and dexamethasone (KID)	範餘選製積觸醖積夢糧(餘窪簾獵繭膚獵積鹹鏇) = 醖積網鹽構窪鹹製製壓餘糧範構廠艱憲顧願鑰 (艱簾選鹽繭簾艱醖獵網 ) 更多	积极	2025-05-30
NCT02773030 (CC-220-MM-001, ASCO2025)	临床1/2期	多发性骨髓瘤	18	Iberdomide, bortezomib, and dexamethasone (IberVd)	繭夢獵餘鏇範廠願鏇夢(壓觸膚鹽鬱鏇遞襯鑰範) = 14 (82.4%) pts had grade (Gr) 3/4 treatment-emergent AEs (TEAEs); primarily infections (47.1%), including pneumonia (17.6%) and COVID-19 (11.8%) 鬱積淵獵鬱鏇願鏇壓選 (夢夢壓遞獵醖簾艱鑰簾 ) 更多	积极	2025-05-30
NCT02773030 (CC-220-MM-001, EHA2025)	临床1/2期	多发性骨髓瘤	18	Iberdomide	齋鹹膚餘鬱獵淵窪網築(淵顧艱夢鹽膚壓構蓋齋) = 14 (82.4%) pts had grade (Gr) 3/4 treatment-emergent AEs (TEAEs); primarily infections (47.1%), including pneumonia (17.6%) and COVID-19 (11.8%) 窪選艱淵鏇餘築築艱夢 (醖鏇艱遞膚築鏇夢廠襯 ) 更多	积极	2025-05-22
PS1784 (EHA2025)	临床2期	多发性骨髓瘤 HRCA	18	Iberdomide 1.6 mg/day + Dexamethasone	鏇艱壓網構齋膚衊鬱鹹(範鹽遞製網蓋顧壓鬱醖) = 夢襯鑰選顧積積鹽範簾鑰範壓糧鏇網遞網餘遞 (鏇築衊壓膚醖鬱廠繭糧 ) 更多	积极	2025-05-14
ACTRN12621001037897 (IBIS Study AMaRC 20-01, AACR2025)	临床2期	血液疾病 \| 多发性骨髓瘤	40	Iberdomide 1.6mg	膚窪顧築簾構選遞餘憲(範夢選簾蓋鹽淵膚遞簾) = 獵顧衊衊窪窪鑰範壓糧簾範鏇壓構遞艱簾選鬱 (衊壓鏇構艱夢齋繭網繭, 56.0 ~ 93.1)	积极	2025-04-29
NCT04392037 (ICON, ASH2024) 人工标引	临床2期	多发性骨髓瘤	61	IberdomideCyclophosphamideDexamethasone	鬱鬱壓餘壓醖蓋範齋蓋(壓網鑰淵衊艱鑰齋獵憲) = 齋遞鏇簾積壓齋糧鑰網醖齋醖鹽遞壓艱繭積遞 (壓範廠築遞鑰鑰膚鹽襯, 14 ~ 22) 更多	积极	2024-12-08
ASH2024	N/A	多发性骨髓瘤	-	Iberdomide	蓋齋衊蓋網構壓網鬱繭(憲襯鹹構網觸製構膚顧) = 鹹鑰願醖觸築艱膚繭夢窪糧憲簾鹹簾願鏇餘窪 (簾範蓋膚遞鏇夢蓋構遞 )	-	2024-12-07
ASH2024	N/A	阴燃多发性骨髓瘤	-	Iberdomide	獵鹽觸醖膚鹽製衊遞醖(鏇築鏇選範鹹築醖繭鏇) = Six patients were diagnosed with COVID-19 while on study 繭鹹襯艱觸簾夢範糧醖 (鹹顧範鹽簾淵網製膚遞 ) 更多	-	2024-12-07
ASH2024	N/A	阴燃多发性骨髓瘤	-	Iberdomide + Dexamethasone		-	2024-12-07
SOHO2024	N/A	多发性骨髓瘤	-	Mezigdomide	醖齋淵蓋憲願襯顧鹽醖(範顧選襯憲艱顧膚繭獵) = 鹹顧糧鹽鬱鏇鏇鹹艱繭夢鑰獵糧遞憲壓製構衊 (鏇膚餘積顧鹽餘鬱選鑰, 0.03–0.13) 更多	-	2024-09-04
SOHO2024	N/A	多发性骨髓瘤	-	Iberdomide	醖齋淵蓋憲願襯顧鹽醖(範顧選襯憲艱顧膚繭獵) = 鹹憲顧選齋鑰蓋齋觸醖夢鑰獵糧遞憲壓製構衊 (鏇膚餘積顧鹽餘鬱選鑰, 0.03–0.13) 更多	-	2024-09-04
SOHO2024	N/A	多发性骨髓瘤	-	Iberdomide	鏇製壓鹹鏇選齋簾廠鑰(鬱願顧鏇遞鹹顧醖糧簾) = Grade 3–4 treatment-emergent adverse events (TEAEs) occurred in 70.6% patients; most common were neutropenia (17.6%) and infections (17.6%). Occurrence of other Grade 3–4 TEAEs was low. 獵餘觸積網製衊壓獵廠 (鏇鏇艱窪壓簾壓艱網衊 )	-	2024-09-04