A Phase 1, Open-Label, Dose Escalation and Dose Expansion Study Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Effects of Orally Administered CB-5083 in Subjects With Advanced Solid Tumors

This is a multicenter, open-label, Phase 1 study of orally administered CB-5083 in adult subjects with advanced metastatic solid tumors. The study will be conducted in 2 parts: an initial Dose Escalation Phase (Phase 1a) of CB-5083 in subjects with advanced metastatic solid tumors who have progressed or are non-responsive to available therapies and for which no standard therapy exists, followed by a Dose Expansion Phase (Phase 1b) which will include 1 to 4 arms: one arm in subjects with RAS mutated mCRC; optionally, at sponsors discretion, 3 additional arms may be added for subjects with advanced RCC, advanced pNET, or solid tumors with mutations in the RAS-MAPK pathway.

开始日期2014-10-11

申办/合作机构

Cleave Therapeutics, Inc.

NCT02223598 / Terminated临床1期

A Phase 1, Dose-Escalation/Dose-Expansion Study Evaluating the Safety, Pharmacokinetics and Pharmacodynamic Effects of Orally Administered CB-5083 in Subjects With Lymphoid Hematological Malignancies

The purpose of this study is to determine the safety, tolerability, dose limiting toxicities, and maximum tolerated dose of CB-5083 in subjects with lymphoid hematological malignancies.

开始日期2014-08-25

申办/合作机构

Cleave Therapeutics, Inc.

100 项与 CB-5083 相关的临床结果

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100 项与 CB-5083 相关的转化医学

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100 项与 CB-5083 相关的专利（医药）

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项与 CB-5083 相关的文献（医药）

2024-06-01·BIOMEDICINE & PHARMACOTHERAPY

Exploring in vivo combinatorial chemo-immunotherapy: Addressing p97 suppression and immune reinvigoration in pancreatic cancer with tumor microenvironment-responsive nanoformulation

Article

作者: Lo, Yu-Li ; Yang, Ching-Ping ; Wu, Li-Ling ; Li, Ching-Yao ; Chang, Yih-Hsin ; Chen, Chun-Jung ; Chou, Tsui-Fen

Pancreatic ductal adenocarcinoma (PDAC) has an extremely devastating nature with poor prognosis and increasing incidence, making it a formidable challenge in the global fight against cancer-related mortality. In this innovative preclinical investigation, the VCP/p97 inhibitor CB-5083 (CB), miR-142, a PD-L1 inhibitor, and immunoadjuvant resiquimod (R848; R) were synergistically encapsulated in solid lipid nanoparticles (SLNs). These SLNs demonstrated features of peptides targeting PD-L1, EGFR, and the endoplasmic reticulum, enclosed in a pH-responsive polyglutamic (PGA)-polyethylene glycol (PEG) shell. The homogeneous size and zeta potential of the nanoparticles were stable for 28 days at 4°C. The study substantiated the concurrent modulation of key pathways by the CB, miR, and R-loaded nanoformulation, prominently affecting VCP/Bip/ATF6, PD-L1/TGF-β/IL-4, -8, -10, and TNF-α/IFN-γ/IL-1, -12/GM-CSF/CCL4 pathways. This adaptable nanoformulation induced durable antitumor immune responses and inhibited Panc-02 tumor growth by enhancing T cell infiltration, dendritic cell maturation, and suppressing Tregs and TAMs in mice bearing Panc-02 tumors. Furthermore, tissue distribution studies, biochemical assays, and histological examinations highlighted enhanced safety with PGA and peptide-modified nanoformulations for CB, miR, and/or R in Panc-02-bearing mice. This versatile nanoformulation allows tailored adjustment of the tumor microenvironment, thereby optimizing the localized delivery of combined therapy. These compelling findings advocate the potential development of a pH-sensitive, three-in-one PGA-PEG nanoformulation that combines a VCP inhibitor, a PD-L1 inhibitor, and an immunoadjuvant for cancer treatment via combinatorial chemo-immunotherapy.

2024-03-01·Stem cell reports

ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons

Article

作者: Johnson, Michelle A ; Antonoudiou, Pantelis ; Paulo, Joao A ; Raman, Malavika ; Klickstein, Jacob A ; Gygi, Steve P ; Weihl, Chris ; Maguire, Jamie

Mutations in the AAA+ ATPase p97 cause multisystem proteinopathy 1, which includes amyotrophic lateral sclerosis; however, the pathogenic mechanisms that contribute to motor neuron loss remain obscure. Here, we use two induced pluripotent stem cell models differentiated into spinal motor neurons to investigate how p97 mutations perturb the motor neuron proteome. Using quantitative proteomics, we find that motor neurons harboring the p97 R155H mutation have deficits in the selective autophagy of lysosomes (lysophagy). p97 R155H motor neurons are unable to clear damaged lysosomes and have reduced viability. Lysosomes in mutant motor neurons have increased pH compared with wild-type cells. The clearance of damaged lysosomes involves UBXD1-p97 interaction, which is disrupted in mutant motor neurons. Finally, inhibition of the ATPase activity of p97 using the inhibitor CB-5083 rescues lysophagy defects in mutant motor neurons. These results add to the evidence that endo-lysosomal dysfunction is a key aspect of disease pathogenesis in p97-related disorders.

2024-01-01·International journal of biological macromolecules

An innovative nanoformulation utilizing tumor microenvironment-responsive PEG-polyglutamic coating and dynamic charge adjustment for specific targeting of ER stress inducer, microRNA, and immunoadjuvant in pancreatic cancer: In vitro investigations

Article

作者: Li, Ching-Yao ; Lo, Yu-Li ; Chou, Tsui-Fen

Pancreatic ductal adenocarcinoma (PDAC) is a significant obstacle to lowering global cancer deaths. CB-5083, a novel valosin-containing protein (VCP)/p97 inhibitor that disrupts proteasomal degradation and induces endoplasmic reticulum stress (ERS) accumulation, was evaluated as an inducer of immunogenic cell death (ICD) in PDAC treatment. Furthermore, miR-142 enhances checkpoint blockade and promotes M1 repolarization, while Toll-like receptor 7/8 agonist resiquimod (R) acts as an immunoadjuvant to amplify the immune response to miR-142. This research signifies the first integration of CB, miR-142, and R in solid lipid nanoparticles (SLNs) modified with peptides targeting PD-L1, EGFR, and ER, which were shelled by the PEG-polyglutamic (PGA) coating that detaches in response to the acidic pH values in the tumor microenvironment (TME). The modified SLNs exhibited pH-sensitive cytotoxicity against Panc-02 cells, preserving normal cells and preventing hemolysis. The innovative approach simultaneously modulated pathways, including VCP/Bip/K48-Ub/ATF6, IRE1α/XBPs/LC3II, PD-L1/TGF-β/IL-10/CD206/MSR1/Arg1, and TNF-α/IFN-γ/IL-6/iNOS/COX-2. Combined treatment blocked VCP, arrested the cell cycle, inhibited EMT, triggered ERS-mediated autophagy/apoptosis, and stimulated robust ICD via the release of damage-associated molecular patterns. This adaptable nanoformulation, displaying pH-sensitive PEG-PGA de-coating and precisely targeting EGFR, PD-L1, and ER, serves to hinder EMT and immune evasion, subsequently amplifying ICD in PDAC cells and the TME.

项与 CB-5083 相关的新闻（医药）

2024-10-27

·生物探索

JCI丨唐晓芳等揭示内质网膜蛋白复合体调控肺表面活性蛋白C突变体SP-C(I73T)的转运并可作为间质性肺病的潜在治疗靶点

引言间质性肺病（ILD）是超过200多种肺部疾病的统称。这些疾病以肺间质炎症和纤维化为特征，对人类健康的危害可与肺癌相提并论，目前尚缺乏对其有效的临床治疗方案。肺表面活性蛋白C（SP-C）的编码基因SFTPC突变引发的肺部稳态的破坏是多种间质性肺病的重要原因，其中最常见的突变为SP-C蛋白序列73位异亮氨酸到苏氨酸的错义突变（I73T）。SP-C由肺泡上皮AT2细胞特异性合成和分泌，已有研究结果表明，SP-C (I73T) 突变蛋白具有细胞毒性，造成AT2细胞的蛋白质稳态破坏和细胞功能障碍，最终导致常染色体显性间质性肺病，临床表现为轻度呼吸道症状、婴儿期/儿童期呼吸衰竭和成人特发性肺纤维化（IPF）。目前由SFTPCI73T遗传突变导致间质性肺病发生发展的具体机制尚不清楚，除肺移植外尚无有效治疗手段。 2024年10月15日， Jeffrey A. Whitsett团队与粤港澳大湾区精准医学研究院（广州）/复旦大学的唐晓芳团队合作在Journal of Clinical Investigation杂志上发表了题为EMC3 regulates trafficking and pulmonary toxicity of the SFTPCI73T mutation associated with interstitial lung disease的研究论文，揭示了EMC复合体关键亚基EMC3调控AT2细胞中SP-C(I73T)突变蛋白的异常转运及相关的AT2细胞毒性损伤，进而导致间质性肺病发生的作用机制，并为SFTPCI73T突变相关的间质性肺疾病提供了潜在的治疗靶点。在本研究中，研究人员建立了一种新的SftpcI73T敲入小鼠模型，并通过对I73T突变小鼠肺部的形态学、生化和蛋白质组学分析证明该模型表现出一系列与SFTPCI73T间质性肺病相关的病理缺陷，包括SP-C (I73T) 前体蛋白的错误加工、异常运输和在细胞膜上的大量积累，以及肺泡结构简化等。基于团队前期对肺发育中EMC3功能的研究工作，研究人员进一步研究了EMC3缺失对SftpcI73T敲入小鼠的影响。在新生与成年的突变小鼠肺部AT2细胞内特异性敲除EMC3后，突变小鼠的肺部结构与生理功能都得到了极大改善。同时，虽然EMC3缺失并不一定影响SP-C (I73T) 前体蛋白的错误加工和整体蛋白水平，但是SP-C (I73T) 前体蛋白在细胞膜上的异常积累大大减少。通过整合蛋白质组学分析以及细胞能量代谢检测结果，研究人员提出SFTPCI73T突变的主要致病机制：SP-C(I73T)突变蛋白在EMC3的参与调控下被错误地运输并累积在细胞膜处，从而破坏了AT2细胞内囊泡运输途径并造成线粒体功能障碍。为进一步研究EMC3的调控作用及挖掘间质性肺病治疗靶点，研究人员借助亲和纯化-质谱筛选了EMC3相互作用的蛋白分子并鉴定出AT2细胞中EMC3的一种主要互作蛋白，VCP（Valosin Containing Protein）。除突变小鼠模型外，研究人员还利用SFTPCI73T患者特异性iPSCs（I73T/Td）及其经过基因校正的对照iPSCs（WT/Td）分别诱导分化为AT2细胞作为体外模型进一步研究EMC3/VCP缺失对SP-C (I73T) 的影响。结果显示，抑制EMC3表达或靶向VCP的小分子抑制剂CB5083处理均可有效改善突变蛋白的异常转运与线粒体功能障碍等病理表现，同时将患者AT2细胞形成的实心球状结构恢复到对照 AT2细胞类似的单层肺泡球形态。本研究不仅为间质性肺病的分子机制提供了新的思路，也为预防和治疗SFTPCI73T相关间质性肺病提供了新的靶点。参考文献 https://www.jci.org/articles/view/173861 责编|探索君排版|探索君来源|BioArt End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

临床1期临床终止

2024-08-07

·生物探索

NI丨周兆才/焦石联合团队发现靶向p97-Npl4复合物组装选择性抑制肿瘤浸润Treg细胞以发展更安全有效的抗肿瘤免疫策略

引言调节性T细胞（Treg）能够抑制针对自身抗原的异常免疫反应，防止免疫系统过度活化，对于维持机体免疫耐受和避免自身免疫性疾病至关重要。在恶性肿瘤微环境中，Treg也是介导免疫逃逸从而促进肿瘤进展，导致肿瘤免疫治疗耐药甚至疾病超进展的关键因素【1】。一系列靶向Treg的药物已处于临床前和临床研究阶段。然而，系统性靶向清除Treg细胞往往导致严重的自身免疫毒副作用，严重阻碍了靶向Treg细胞的肿瘤免疫疗法在临床上的实际应用。因此，如何在不破坏系统免疫稳态的前提下，选择性靶向肿瘤浸润Treg（TI-Treg）细胞以增强抗肿瘤免疫反应，是该领域面临的重大挑战。 p97 (VCP) 属于AAA-ATP酶家族，可与多种辅因子蛋白结合，广泛参与调控细胞内泛素化蛋白降解、DNA修复、核膜重构、细胞周期以及自噬等一系列生命过程。其中，Npl4是p97发挥功能最重要的辅因子之一。p97与Npl4形成的复合物能够识别和抽取泛素化的蛋白底物，并将其运送到蛋白酶体进行降解，对细胞内蛋白稳态维持至关重要【2】。近年来，p97作为一个抗癌药物靶点而颇受关注，其中一些靶向p97直接杀伤肿瘤细胞的候选药物已进入临床研究阶段。然而，这些p97抑制剂（如CB-5083）大多针对其ATP酶活催化中心，从而将阻断或干扰所有p97介导的细胞生物学过程，甚至包括那些在免疫细胞中尚未被阐明的功能。因此，无差别抑制p97酶活性极有可能导致副作用。 2024年8月6日，复旦大学生命科学学院周兆才教授和焦石青年研究员合作在国际学术期刊Nature Immunology在线发表题为Targeting p97-Npl4 interaction inhibits tumor Treg cell development to enhance tumor immunity【3】的研究论文，发现通过靶向p97与Npl4之间的相互作用能够选择性抑制TI-Treg细胞增强抗肿瘤免疫应答，而不破坏机体的系统免疫稳态。该研究团队于2015年报道了p97-Npl4复合物调控RIG-I抗病毒免疫应答的非经典功能【4】；并在此基础上，推断靶向p97-Npl4复合物分子界面（而不是p97酶活催化中心），有望开发特异性更强，毒副作用更小的先导化合物。在此思路指导下，研究团队首先通过AlphaScreen高通量筛选，从8,120种FDA批准的药物中筛选出能够打破p97-Npl4相互作用的化合物Thonzoniumbromide (TB)。之后的体外肿瘤细胞增殖和体内裸鼠成瘤实验均显示TB与CB-5083具有类似的抗癌效果。然而，在一系列免疫健全的小鼠肿瘤模型中，TB均展示出比CB-5083更强的抗癌活性。由此，研究团队猜测TB在体内除了像CB-5083一样直接杀伤肿瘤细胞之外，可能还参与调控了肿瘤免疫。进一步的单细胞测序分析表明TB确实重塑了肿瘤免疫微环境，显著促进了CD8+ T细胞的抗肿瘤活性。同时，T细胞过继转移实验也证实TB抗肿瘤活性很大程度上依赖于T细胞。为了明确TB靶向p97-Npl4互作发挥肿瘤免疫调控功能的具体细胞类型，研究团队根据前期解析的p97-Npl4复合物的三维结构信息【4】，构建了破坏p97与Npl4复合物组装的条件性p973A突变敲入小鼠。研究人员将p973A突变引入CD4+ T细胞之后，却发现其对肿瘤生长并无显著影响。于是，他们又对T细胞的不同亚群进行详细分析，结果发现TB处理显著抑制了肿瘤浸润Treg细胞数量，同时大大促进了Th17细胞数量。进一步，在Treg细胞中特异性敲入p973A突变体之后，肿瘤生长受到显著抑制，伴随TI-Treg数量明显降低而Th17细胞增多。值得注意的是，靶向p97-Npl4复合物组装抑制Treg细胞具有肿瘤特异性，而对外周Treg细胞和机体系统免疫稳态并无显著影响。最后，研究团队深入解析了p97-Npl4复合物通过招募E3泛素连接酶PDLIM2/5促进Stat3泛素化降解，从而调控Treg-Th17分化平衡的分子机制。总而言之，该研究发现了p97-Npl4复合物通过Stat3调控Treg-Th17细胞分化平衡的功能作用；提供了一种选择性抑制肿瘤浸润Treg而不破坏机体系统免疫稳态的肿瘤免疫治疗新策略。图1. 靶向p97-Npl4相互作用选择性抑制肿瘤浸润Treg细胞（Credit: Nature Immunology）参考文献 1. Tay, C., Tanaka, A. & Sakaguchi, S. Tumor-infiltrating regulatory T cells as targets of cancer immunotherapy. Cancer Cell 41, 450-465 (2023). 2. Skrott, Z. et al. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature 552, 194-199 (2017). 3. Nie, P. et al. Targeting p97–Npl4 interaction inhibits tumor Treg cell development to enhance tumor immunity. Nature Immunology (2024). 4. Hao, Q. et al. A non-canonical role of the p97 complex in RIG-I antiviral signaling. EMBO J 34, 2903-2920 (2015). https://www.nature.com/articles/s41590-024-01912-y 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

免疫疗法临床研究

100 项与 CB-5083 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
晚期恶性实体瘤	临床1期	美国	Cleave Therapeutics, Inc.	2014-10-11
多发性骨髓瘤	临床1期	美国	Cleave Therapeutics, Inc.	2014-08-25
多发性骨髓瘤	临床1期	加拿大	Cleave Therapeutics, Inc.	2014-08-25