预约演示

更新于：2025-07-14

Sabatolimab

更新于：2025-07-14

概要

概要

基本信息

药物类型

单克隆抗体

别名

Anti-tim-3 monoclonal antibody mbg453、Anti-tim3 checkpoint inhibitor mbg453、Immunoglobulin g4 (226-proline,de-c-terminal-lysine), anti-(human hepatitis virus a cellular receptor 2) (human-mus musculus monoclonal clone nvs260714 .gamma.4-chain), disulfide with human-mus musculus monoclonal clone nvs260714 .kappa.-chain, dimer

+ [3]

靶点

TIM3

作用方式

抑制剂

作用机制

TIM3抑制剂(甲型肝炎病毒细胞受体2抑制剂)

治疗领域

肿瘤血液及淋巴系统疾病神经系统疾病+ [2]

在研适应症

多形性胶质母细胞瘤Snyder-Robinson综合征白血病前期+ [1]

非在研适应症

晚期恶性实体瘤慢性粒单核细胞白血病黑色素瘤+ [5]

原研机构

CoStim Pharmaceuticals, Inc.

在研机构

Novartis Pharmaceuticals Corp.

非在研机构

Novartis Pharma AGNovartis Pharma Stein AG诺华（中国）生物医学研究有限公司

权益机构-

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)终止

特殊审评快速通道 (美国)、孤儿药 (欧盟)

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结构/序列

Sequence Code 9911296H

来源: *****

Sequence Code 9911316L

来源: *****

关联

项与 Sabatolimab 相关的临床试验

NCT06664879

/ Recruiting临床1/2期

ALLG AMLM26 INTERCEPT (Investigating Novel Therapy to Target Early Relapse and Clonal Evolution as Pre-emptive Therapy in AML): A Multi-arm, Precision-based, Recursive, Platform Trial

To demonstrate the efficacy of targeted and tailored sequential therapy in patients with AML.

开始日期2024-12-30

申办/合作机构

Australasian Leukaemia & Lymphoma Group

NCT05367401

/ Withdrawn临床1/2期

A Phase Ib/II, Open Label, Proof-of-concept Study of Sabatolimab and Magrolimab-based Therapy for Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome

This study is to determine the safety and preliminary efficacy of sabatolimab in combination with magrolimab and azacitidine in adult participants with 1L unfit Acute Myeloid Leukemia (AML) or with 1L higher risk Myelodysplastic Syndromes (MDS), and sabatolimab in combination with magrolimab in participants with relapsed or refractory (R/R) AML.

开始日期2024-12-20

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT05201066

/ Active, not recruiting临床2期

An Open-label, Multicenter, Roll-over Study for Patients Who Have Completed a Prior Novartis-sponsored Sabatolimab (MBG453) Study and Are Judged by the Investigator to Benefit From Continued Treatment With Sabatolimab.

This study is intended to collect safety data from participants who completed the parent protocols but are still benefiting from study treatment. The study population consists of participants who tolerate study treatment of the parent studies. Collecting safety information from long-term exposure might offer the unique opportunity to detect rare Adverse Events.

开始日期2023-02-13

申办/合作机构

Novartis Pharmaceuticals Corp.

100 项与 Sabatolimab 相关的临床结果

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100 项与 Sabatolimab 相关的转化医学

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100 项与 Sabatolimab 相关的专利（医药）

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项与 Sabatolimab 相关的文献（医药）

2024-12-01·LEUKEMIA

Managing the unmanageable: evidence-driven approaches to real-world patient prototypes of TP53-mutant myelodysplastic neoplasms and acute myeloid leukemia

Review

作者: Patel, Shyam A ; Patel, Shyam A.

Patients with TP53 aberrations comprise the highest risk subset of all myeloid malignancies. The managerial conundrum of TP53-mutant myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) stems from refractoriness to or relapse after conventional chemotherapy, as well as the limited translational success of investigational therapies targeting TP53-mutant cells. Thus far, no targeted therapies have been commercially approved for this mutational subset. As a result, management plans for patients with TP53-mutant MDS and AML are often driven by clinical judgment and/or physician preference rather than consensus guidelines backed by a rigorous evidence basis. This clinical case-based, evidence-driven review highlights the most salient data that guides the management of commonly encountered patient prototypes. This review discusses the therapeutic menu of first-line options that derive from multi-institutional experiences as well as from disease-centric consortia and discusses how these first-line options can be optimally tailored to heterogeneous groups of patients. The debate regarding whether allogeneic stem cell transplant should be offered to these patients is summarized. Finally, this review explores the recent unfortunate news of pauses in clinical trials for the leading investigational agents - eprenetapopt, magrolimab, sabatolimab, and idasanutlin - and offers solutions toward re-invigorating the pipeline of precision therapeutics in 2025.

2024-09-03·CLINICAL CANCER RESEARCH

Correction: Phase I/Ib Clinical Trial of Sabatolimab, an Anti–TIM-3 Antibody, Alone and in Combination with Spartalizumab, an Anti–PD-1 Antibody, in Advanced Solid Tumors

作者: Bedard, Philippe L. ; Xyrafas, Alexandros ; Sabatos-Peyton, Catherine A ; Mach, Nicolas ; Sabatos-Peyton, Catherine A. ; Curigliano, Giuseppe ; Longmire, Tyler A. ; Manenti, Luigi ; Curigliano, Hans ; Forde, Patrick M. ; Sun, Haiying ; Naing, Aung ; Sarantopoulos, John ; Doi, Toshihiko ; Tai, David ; Hodi, F Stephen ; Santoro, Armando ; Wilgenhof, Sofie ; Lin, Chia-Chi ; Gutzwiller, Sabine ; Hodi, F. Stephen ; Forde, Patrick M ; Bedard, Philippe L ; Longmire, Tyler A

2024-08-01·BMJ Open

Sabatolimab in combination with spartalizumab in patients with non-small cell lung cancer or melanoma who received prior treatment with anti-PD-1/PD-L1 therapy: a phase 2 multicentre study

Article

作者: Lin, Chia-Chi ; Xyrafas, Alexandros ; Curigliano, Giuseppe ; Pastore, Alessandro ; Sabatos-Peyton, Catherine ; Mach, Nicolas ; Kim, Dong-Wan ; Chitnis, Shripad ; Tai, David ; Santoro, Armando ; Gutzwiller, Sabine ; Doi, Toshihiko ; Szpakowski, Sebastian ; Wilgenhof, Sofie ; Hodi, F Stephen

Objective:

This study evaluates the safety/efficacy of sabatolimab plus spartalizumab in patients with melanoma or non-small cell lung cancer (NSCLC).

Design, setting and participants:

This is a phase 1–1b/2, open-label, multinational, multicentre study of patients with advanced/metastatic melanoma or NSCLC with ≥1 measurable lesion.

Interventions:

Patients were given sabatolimab 800 mg every 4 weeks plus spartalizumab 400 mg every 4 weeks until unacceptable toxicity, disease progression and/or treatment discontinuation.

Outcome measures:

The phase 2 primary outcome measure was overall response rate and secondary objectives included evaluation of the safety, tolerability, efficacy and pharmacokinetics of sabatolimab in combination with spartalizumab.

Results:

33 patients (melanoma n=16, NSCLC n=17) received sabatolimab plus spartalizumab. 31 (94%) experienced ≥1 adverse event (AE); 15 (46%) experienced grade 3/4 events. The most frequent grade ≥3 AEs for NSCLC were anaemia, dyspnoea and pneumonia (each n=2, 12%); for patients with melanoma, the most frequent grade ≥3 AEs were physical health deterioration, hypokalaemia, hypophosphataemia, pathological fracture and tumour invasion (each n=1; 6%). One (3%) patient discontinued treatment due to AE. Stable disease was seen in three patients with melanoma (19%) and six patients with NSCLC (35%). Median progression-free survival was 1.8 (90% CI 1.7 to 1.9) and 1.7 (90% CI 1.1 to 3.4) months for patients with melanoma and NSCLC, respectively. Patients with stable disease had higher expression levels of CD8, LAG3, programmed death-ligand 1 and anti-T-cell immunoglobulin and mucin-domain containing-3 at baseline. The pharmacokinetics profile of sabatolimab was consistent with the phase 1 study.

Conclusions:

Sabatolimab plus spartalizumab was well tolerated in patients with advanced/metastatic melanoma or NSCLC who had progressed following antiprogrammed death-1/antiprogrammed death-ligand 1 treatment. Limited antitumour activity was observed. The tolerability of sabatolimab administration supports the potential to explore treatment with sabatolimab in various combination regimens and across a spectrum of tumour types.

Trial registration number:

NCT02608268.

项与 Sabatolimab 相关的新闻（医药）

2025-06-17

·抗体圈

重磅炸弹翻车

近日，一个大靶点的代表性管线有了新的核心进展。2025年6月16日，艾伯维宣布Bcl-2抑制剂维奈克拉+阿扎胞苷联合一线治疗高危骨髓增生异常综合征（HR-MDS）的三期临床VERONA没有达到OS主要终点，HR为0.908，p值为0.3772。维奈克拉拓展适应症，宣告失败。Bcl-2靶点的first in class在HR-MDS上的失败，会不会影响国内管线的整体布局，该适应症的市场，又有几何？01Bcl-2发家要了解Bcl-2抑制剂，首先先详细对Bcl-2本身进行了解。Bcl-2是Bcl-2调节蛋白家族的创始成员，在该家族之中，一些成员抑制细胞凋亡，而另一些成员则促进细胞死亡。恰好Bcl-2蛋白属于抑制细胞凋亡的类型。如图所示，BCL-2及其他拮抗凋亡蛋白通过直接结合BAX和BAK起抑制凋亡作用。从这个逻辑去推，Bcl-2如果异常高表达的话，那么细胞就没办法正常凋亡了。于是，如果细胞内这种蛋白质调高，没办法正常凋亡了呢？这就是问题所在了，没办法正常凋亡而堆积如山的细胞，就成了癌细胞。拮抗和促进细胞凋亡的BCL-2家族蛋白之间的相互作用和动态平衡决定着细胞的生死，细胞是否开始凋亡过程取决于细胞内各种促进和拮抗凋亡信号的整合，正常情况下细胞凋亡过程被严格调控，而这一过程在很多血液系统恶性肿瘤中被破坏。因此，得想办法抑制Bcl-2的表达。根据文献《BCL-2抑制剂在血液系统恶性肿瘤中的研究进展》，BCL-2的功能可被BH3-only蛋白抑制，BH3-only蛋白结合BCL-2位点同时也是BAX与BCL-2的结合位点，因此一个合理的抗癌药物设计思路便是设计BH3类似物。而维奈克拉，是第一个BCL-2选择性BH3类似物。维奈克拉破坏了其与促凋亡蛋白（如BAX、BAK和BIM）的相互作用，使这些蛋白能够诱导线粒体外膜通透性，从而导致细胞色素c的释放、胱天蛋白酶的激活和细胞凋亡。2011年，维奈克拉开始了一系列的临床试验，而它的宿敌为慢性淋巴细胞白血病（CLL）与急性髓性白血病（AML）。其代号为VIALE的临床试验，随后拉开了序幕。VIALE-A为阿扎胞苷和维奈克拉联用在一线治疗AML。主要终点上，阿扎胞苷-维奈克拉组的中位总生存期为14.7个月，对照组（化疗组）为9.6个月，HR值为0.66。安全性上，阿扎胞苷-维奈克拉组235例患者（83%）和对照组105例患者（73%）发生严重不良事件。这个严重不良反应发生率还是有些高的。此外，还有一项AML适应症的三期临床——VIALE-C。这一临床试验上，该试验专为无法接受强化诱导治疗的新诊断AML患者而设计。旨在评估维奈克拉和阿糖胞苷的组合是否比安慰剂和阿糖胞苷联合使用更能改善OS。最后mOS的HR为0.75，P=0.11，没能达到临床试验终点。但后来经过6个月的额外随访，经过调整后的mOS的HR为0.7，p=0.04。慢性淋巴细胞白血病的一线治疗呢？根据文章《First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia》，其设计的三期临床非常复杂，1：1：1：1分为了四组，分别接受四种治疗方案去治疗，分别为化学免疫疗法，维奈克拉-利妥昔单抗治疗，维奈克拉-奥比妥珠单抗治疗，接受维奈克拉-奥比妥珠单抗-伊布替尼治疗。最后结果上，经过中位随访期38.8 个月后，mPFS的中期分析显示，维奈克拉-奥比妥珠单抗-伊布替尼联合治疗优于化学免疫治疗，HR为0.32；P<0.001。尽管维奈克拉-奥比妥珠单抗在无进展生存期方面优于化学免疫疗法（HR，0.42；P<0.001），但维奈克拉-利妥昔单抗组与化学免疫疗法组之间无显著差异（HR，0.79；P=0.18）。维奈克拉目前公认的情况来看，单药治疗的疗效是有限的，这是事实，因此目前开的临床基本许多是靠联用。但不能否认的是维奈克拉确实开创了Bcl-2的整整一个时代，获批了CLL、AML等适应症。2024年，其销售额达到了25.83亿美金。02HR-MDS——确实不好出结果本次临床试验上，治疗适应症为高危骨髓增生异常综合征（HR-MDS）。MDS是一组异质性克隆性造血干细胞恶性肿瘤，其特征是骨髓衰竭、转化为急性髓系白血病 (AML) 的风险以及总体生存期 (OS) 缩短。在一线治疗中，化疗药物HMA例如阿扎胞苷(AZA)、地西他滨和口服地西他滨/西达尿苷仍然是标准治疗。在它之上临床试验折戟的药物并不少，如图所示。Eprenetapopt是一种小分子p53稳定剂，与阿扎胞苷联用共同诱导肿瘤细胞死亡。它主要针对的是TP53突变型MDS，约占MDS人群总数的20%。临床II期结果上，MDS 患者中，73%（n=29）的患者有缓解，其中50%（n=20）达到CR。但该药后续就没了下文，因为和阿扎胞苷对比，它的联用并没有表现出很明显的优效性。再之后，它没有再开三期临床。sabatolimab是诺华的TIM-3单抗，其治疗HR-MDS的II期临床试验为STIMULUS-MDS1，最后结果上，mPFS为11.1个月:8.5个月，HR为0.75，p＞0.1，没做出统计学差异。之后它也没有再开三期临床。Magrolimab，这个熟了，吉利德的CD47单抗。本来是二期临床完之后开了三期临床，2023年7月21日，吉利德宣布终止CD47单抗Magrolimab联合阿扎胞苷治疗高风险骨髓增生异常综合征（MDS）的3期临床Enhance研究，原因是疗效不佳。由此我们可以看到，维奈克拉的失败，真的不能只怪维奈克拉，这个适应症本身，现在都还没有在它上面做出不错对比疗效的新药，啃不下来，不足为奇。03下一代管线谁与争锋但HR-MDS仍是不可小觑的适应症。其在中老年患者高发，尤其在60岁以上的老年人群体，大部分因身体条件问题对化疗不耐受，仅通过替换受损的造血干细胞来恢复正常的血液功能（供体有限&配型不合），从而改善MDS症状或实现治愈，未满足临床需求巨大。HR-MDS市场潜力同样不可小觑，数据显示：国内MDS发病率在1.5人/10万人，美国每年MDS新发患者在2-4万人，其中仅高危MDS预期市场规模就在10-20亿美元。维奈克拉折戟后，国内外不少玩家也瞄准了这个潜力市场。国内最为知名的Bcl-2抑制剂研发biotech就是亚盛医药了，它的APG-2575在FDA获得了5个孤儿药资格认定，分别为华氏巨球蛋白血症、慢性淋巴细胞白血病、多发性骨髓瘤、急性髓系白血病和滤泡性淋巴瘤。都是非常经典的骨髓白血病，也是比较对照化疗比较容易做出结果的适应症。不过，它也在啃HR-MDS这块硬骨头。根据2024年ASH大会上的数据，HR-MDS患者的ORR为50%（1/2），样本量太小，目前还不太好下结论，不过它目前已经在准备三期临床了，其名为GLOR-A-4，已获国家药品监督管理局药物审评中心临床试验许可，预计在2029年达到临床主要终点。此外，还有别的靶点在这个适应症上深耕，比较典型的是康方的AK117。它已经在HR-MDS上出了临床Ib期数据，根据临床Ib期数据，27例可评估患者中CR率为48.1%（不同剂量组下），在24例随访≥3个月的可评估患者中，CR率进一步升至54.2%。13例最初需要红细胞（RBC）输注的可评估患者中，8例（61.5%）最终不再依赖红细胞输注。而同靶点的知名管线则是宜明昂科的IMM01，也随后出了结果，51例疗效可评估患者中，ORR为64.7%，其中CR率为29.4%。目前的肩对肩比较来看，康方的同靶点数据更胜一筹。当然，国外也有公司有新的消息。Bexmarilimab为靶向Clever-1的抗体，机制上来说，通过阻断巨噬细胞上的Clever-1可以增强抗原呈递和T细胞活化。由于Clever-1在髓系白血病细胞上表达，Bexmarilimab因此具有抗白血病作用。该药已在MDS适应症上授予孤儿药认定，其二期临床已经达到了终点，Bexmarilimab联合阿扎胞苷治疗方案在R/R MDS患者中取得63%的ORR，在初治患者中达到76%的ORR。不过该适应症，最终还是需要三期临床对比阿扎胞苷单药的验证。无论何时都不能半场开香槟。结语：总的来说，维奈克拉凭借一己之力，单独为bcl-2开创了一个时代。不能因为它在一个大家都失败的适应症上折戟，就否认它的价值。接下来，该轮到下一波血液疾病管线梯队上了。识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！请注明：姓名+研究方向！本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

临床3期临床结果临床失败临床2期

2024-04-11

·SYNAPSE

Summary of Global Clinical Trial Failures in January 2024

1.Theravance Biopharma: Yupelri (revfenacin)Indication: Chronic Obstructive Pulmonary Disease (COPD) Clinical Trials: Phase 4 On January 5th, Theravance Biopharma announced that the Phase IV PIFR-2 study of Yupelri (revefenacin) inhalation solution for the maintenance treatment of Chronic Obstructive Pulmonary Disease (COPD) did not meet the primary endpoint. Yupelri is the only once-daily nebulized long-acting muscarinic antagonist (LAMA) approved in the United States for the maintenance treatment of COPD. The PIFR-2 study aimed to evaluate the improvement in lung function of Yupelri as compared to tiotropium bromide (Spiriva, a dry powder inhaler) in patients with severe to very severe COPD. The study results showed that on day 85, there was no statistically significant difference in the primary endpoint of change from baseline in trough Forced Expiratory Volume in one second (FEV1) compared to the control group. The safety and tolerability profile of Yupelri was consistent with previous studies. 2. Novartis: LigelizumabIndication: peanut allergy Clinical Trials: Phase 3 On January 16th, the clinicaltrials.gov website indicated that Novartis has discontinued the Phase III clinical trial for the treatment of peanut allergy with the immunoglobulin E (IgE) monoclonal antibody Ligelizumab (study CQGE031G12301). This study was a multicenter, randomized, double-blind, placebo-controlled clinical trial, which initially aimed to enroll 486 patients medically diagnosed with IgE-mediated peanut allergy, to evaluate the efficacy and safety of Ligelizumab (120/240mg, once a month) compared to a placebo. As of the termination date of the trial, 211 patients had been enrolled. This termination marks the second setback encountered by Ligelizumab in the immunotherapy field. In September 2023, Novartis formally terminated the Phase III PEARL-PROVOKE study for the treatment of chronic inducible urticaria (CIU) with Ligelizumab, due to the drug not demonstrating a significant therapeutic advantage in two Phase III studies (PEARL 1 and PEARL 2) for the treatment of chronic spontaneous urticaria (CSU). Although Ligelizumab was more effective than a placebo, it was less effective than omalizumab. 3. Allakos: lirentelimabIndication: Chronic Spontaneous Urticaria Clinical Trials: Phase 2 On January 16th, Allakos announced that lirentelimab did not meet the primary endpoints in the Phase 2 clinical trial (ATLAS) for patients with atopic dermatitis and the Phase 2b clinical trial (MAVERICK) for patients with chronic spontaneous urticaria. The results of the Phase 2b clinical trial (ATLAS) for the treatment of atopic dermatitis patients with lirentelimab showed that, at the primary endpoint after treatment to achieve EASI-75, 23% of patients treated with lirentelimab reached EASI-75 compared to 18% of patients treated with placebo, which was not statistically significant. In the MAVERICK trial, for the primary endpoint on the reduction of the UAS7 score, patients treated with lirentelimab saw a 27% reduction in UAS7 compared to a 26% reduction in the placebo-treated group, which also lacked statistical significance. 4. Gilead: Trodelvy® (sacituzumab-govitecan-hziy; SG)Indication: non-small cell lung cancer (NSCLC) Clinical Trials: Phase 3 On January 22, Gilead announced that its Trop2 ADC (antibody-drug conjugate) new drug, Trodelvy, did not meet the primary OS (overall survival) endpoint in the Phase III clinical trial EVOKE-01 for the treatment of non-small cell lung cancer (NSCLC). EVOKE-01 is assessing the efficacy of the Trop2 ADC drug Trodelvy® (sacituzumab govitecan-hziy; SG) in combination with docetaxel in patients with metastatic or advanced NSCLC who have progressed during or after treatment with platinum-based chemotherapy and checkpoint inhibitors. Trodelvy is a Trop-2 targeting ADC monoclonal antibody drug. Trop-2 is a transmembrane glycoprotein whose high expression is associated with the occurrence of many tumors and poorer prognosis, making it a very popular target for ADC research, second only to HER2 in terms of interest. Currently, Gilead's Trop-2 ADC drug Trodelvy is the only one approved globally for the treatment of adult patients with metastatic triple-negative breast cancer (mTNBC) who have previously received at least two therapies, and for patients with locally advanced or metastatic urothelial carcinoma (UC). 5. BMS: OpdivoIndication: Second Time in Late-Stage Kidney Cancer Clinical Trials: Phase 3 On January 29, Bristol-Myers Squibb (BMS) announced the failure of its PD-1 inhibitor, Opdivo, in Part B of the Phase III CheckMate-914 study, as it did not provide a significant benefit in disease-free survival for patients at high risk of recurrence after local renal cell carcinoma surgery. CheckMate-914 is a randomized, double-blind, two-part trial. In Part B, the study compared monotherapy with Opdivo to a placebo. The trial was designed to assess its use as an adjuvant treatment for renal cell carcinoma (RCC) patients who have undergone complete or partial nephrectomy and are at intermediate or high risk of recurrence. After a median follow-up of 27 months, Opdivo failed to demonstrate a significant improvement in disease-free survival (DFS) as compared to placebo, with a hazard ratio of 0.87 and a p-value of 0.3952 based on an assessment by blinded independent central review (BICR). The 12-month DFS probability for the Opdivo group was 83.3%, compared with 78.2% for the placebo group. At 18 months, these estimates changed only slightly to 78.4% and 75.4%, respectively. At the time of analysis, the median DFS for both treatment groups had not been reached. 6. Laekna: afuresertibIndication: platinum-resistant ovarian cancer (PROC) Clinical Trials: Phase 2 On January 29, Laekna Pharma announced the top-line data from the PROFECTA-II study for the combination of afuresertib with paclitaxel in the treatment of platinum-resistant ovarian cancer (PROC). The PROFECTA-II study (NCT04374630) is a randomized, open-label, active-controlled phase II clinical trial evaluating the efficacy and safety of the combination of afuresertib and paclitaxel compared to paclitaxel alone in female patients with platinum-resistant ovarian cancer (PROC). The study enrolled 150 patients randomly across the United States and China into both the experimental and control groups. The primary endpoint was progression-free survival as assessed by the researchers, while secondary endpoints included overall survival, objective response rate, and duration of response. Trial results indicated that the combination treatment of afuresertib and paclitaxel reduced the risk of disease progression or death (progression-free survival, PFS), with an HR of 0.744 (95% CI: 0.502-1.102); however, the results were not statistically significant. 7. Novartis: sabatolimabIndication: intermediate, high, or very high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia-2 (CMML-2) Clinical Trials: Phase 3 On January 31, in its 2023 financial report, Novartis provided updates on its pipeline progress, revealing that the phase III STIMULUS MDS2 study of its TIM-3 monoclonal antibody, sabatolimab (MBG453), in combination therapy for intermediate, high, or very high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia-2 (CMML-2), did not meet its primary endpoint of overall survival (OS). As a result, Novartis has removed it from its pipeline. Moreover, Novartis has also decided to discontinue the development of the BTK inhibitor remibrutinib for the treatment of Sjögren’s syndrome. TIM-3 is a receptor protein belonging to the T cell immunoglobulin and mucin domain (TIM) family that is expressed on the surfaces of T cells, regulatory T cells (Tregs), and innate immune cells (including dendritic cells, natural killer cells, and monocytes). Previously, Novartis had posited that sabatolimab could act by inhibiting the function of the TIM-3 receptor, thereby targeting both myeloid leukemia cells and immune cells simultaneously. This inhibition was hoped not only to kill cancer cells but also potentially enhance the vigor of immune cells.

2024-02-19

·CPHI制药在线

研发 | 免疫新秀TIM-3研究进展概况

关注并星标CPHI制药在线 TIM3（T 淋巴细胞免疫球蛋白黏蛋白-3）是TIM家族的一个受体蛋白，在T细胞、Treg细胞（T调控细胞）、先天免疫细胞表面表达。TIM3是一类负调控免疫检查点，其作用机制为通过抑制T辅助细胞（Th1和Th7）、诱导CD8+T细胞耗竭、促进Treg细胞成为免疫抑制的细胞群等途径发挥免疫抑制作用。 TIM-3是继PD-1、CTLA-4后，研究较多的免疫治疗靶点之一。研究发现，对于抗PD-1单抗治疗无反应或者产生耐药性的患者往往与TIM-3 的表达高度相关，这一高表达可导致免疫逃逸。因此，针对TIM3和PD1通路的联合用药研究具有广阔前景。虽然TIM-3是目前研究最多的免疫治疗靶点之一，但目前国内外尚无药物获批上市，国内外研发进度靠前的产品如下。诺华：Sabatolimab（MBG453）Sabatolimab（MBG453）是诺华开发的一款直接靶向于TIM-3的人源化IgG4k抗体，用于治疗骨髓增生异常综合征（MDS）和急性髓性白血病（AML），可以创新性地同时靶向髓系白血病细胞和免疫细胞，不但能杀伤癌细胞，而且可能增强免疫细胞的活力，曾被诺华寄予厚望。不过，今年1月底，诺华在财报中宣布，Sabatolimab联合治疗中度、高或极高风险MDS或慢性粒单核细胞白血病-2（CMML-2）的III期研究未达到总生存期（OS）的主要终点。基于此，诺华已决定终止该药物的临床研发，并从公司研发管线中剔除。 GSK：TSR-022TSR-022是由Tesaro公司（被GSK收购）研发的一款人源化抗TIM-3 IgG4抗体，其适应症聚焦于非小细胞肺癌（NSCLC）、肝细胞癌、黑色素瘤等实体瘤。在TSR-022进行单药治疗的临床试验中，31例肿瘤患者达到了疾病稳定（SD），1例平滑肌肉瘤患者出现部分反应（PR），并且未观察到剂量限制毒性。这些数据为TSR-022与PD-1抗体联合治疗奠定了基础。这一推测也在临床试验中得到了验证，在202例PD-1/PD-L1抗体难治的NSCLC患者中，与固定剂量的TSR-042（一种PD-1抗体）联合使用的情况下，随着TSR-022的剂量增加其显示出的临床活性也在增加，且未观察到剂量限制毒性。这说明TSR-022可与 PD-1/PD-L1等抗体起到协同作用，用于治疗PD-1/PD-L1耐药的患者。罗氏：RO7121661罗氏研发的RO7121661是一种TIM-3/PD-1双特异性抗体，可靶向TIM3和PD-1双靶点。目前正在进行一项针对晚期转移性实体瘤患者的 II期研究。恒瑞：SHR-1702SHR-1702是恒瑞研发的一款抗TIM-3单抗，早在2019年，恒瑞就开展了SHR-1702单药或联合PD-1抗体（卡瑞利珠单抗）治疗晚期实体瘤的I期研究，旨在确定SHR-1702单药或联合卡瑞利珠单抗在晚期实体瘤受试者中的剂量限制性毒性与最大耐受剂量等，不过目前该药仍处于I期临床阶段。正大天晴：TQB2618TQB2618是正大天晴研发的一款靶向TIM-3受体的人源化单抗。针对该产品，正大天晴开展了多项临床研究，包括：联合去甲基化药物在复发难治性急性髓系白血病、骨髓增生异常综合征受试者中的I期临床试验；联合抗PD-L1单抗贝莫苏拜单抗（正大天晴研发）在晚期实体瘤患者中的Ib期临床试验；联合贝莫苏拜单抗一线标准治疗失败后的复发广泛期小细胞肺癌患者的Ib/II期临床试验；联合派安普利单抗(正大天晴和康方生物联合研发的一款抗PD-1抗体)治疗复发/转移性鼻咽癌患者的II期临床研究等。百济神州：surzebiclimabsurzebiclimab是百济神州研发的一款抗TIM-3人源化IgG1单克隆抗体，目前正在进行与替雷利珠单抗联用治疗晚期实体瘤的研究。作为免疫检查点的后起之秀，目前开发TIM-3靶点的公司并不多。据不完全统计，目前处于在研阶段的TIM3药物约33款，大部分处于临床前阶段。由于选择性激活TIM-3从而导致免疫逃逸是PD-1抗体免疫治疗过程中发生耐药的主要机制，可见TIM-3抗体应用前景巨大。对TIM-3抗体及其应用的研究还需要进一步探索，目前国内外研发进展相差不大，国内公司或可大有所为。主要参考资料： 1、Romero, Diana. "PD1 says goodbye, TIM3 says hello." Nature Reviews Clinical Oncology 13.4 (2016): 202-203. 2、Ngiow, Shin Foong, et al. "Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors." Cancer research (2011). 3、https://stke-sciencemag-org.libproxy1.nus.edu.sg/content/14/687/eaba0717. 4、BlockingTIM-3 in Treatment-Refractory Advanced Solid Tumors: A Phase Ia/b Study ofLY3321367 with or without an Anti-PD-L1 Antibody.ClinCancer Res2021 Jan 29;clincanres.4405.2020.【智药研习社课程预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

免疫疗法并购临床3期财报临床2期

100 项与 Sabatolimab 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16322

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
慢性粒单核细胞白血病	临床3期	美国	诺华（中国）生物医学研究有限公司	2020-06-08
慢性粒单核细胞白血病	临床3期	美国	Novartis Pharma Stein AG	2020-06-08
慢性粒单核细胞白血病	临床3期	美国	Novartis Pharmaceuticals Corp.	2020-06-08
慢性粒单核细胞白血病	临床3期	美国	Novartis Pharma AG	2020-06-08
慢性粒单核细胞白血病	临床3期	中国	Novartis Pharmaceuticals Corp.	2020-06-08
慢性粒单核细胞白血病	临床3期	日本	Novartis Pharmaceuticals Corp.	2020-06-08
慢性粒单核细胞白血病	临床3期	日本	Novartis Pharma AG	2020-06-08
慢性粒单核细胞白血病	临床3期	日本	诺华（中国）生物医学研究有限公司	2020-06-08
慢性粒单核细胞白血病	临床3期	日本	Novartis Pharma Stein AG	2020-06-08
慢性粒单核细胞白血病	临床3期	阿根廷	Novartis Pharma AG	2020-06-08

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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


NCT04623216 (CTgov)	临床1/2期	急性髓性白血病	24	Sabatolimab (Sabatolimab 400mg Mono Adults)	醖繭選襯積築夢顧窪簾 = 蓋憲網積憲齋襯願鑰網廠蓋鹽繭糧鬱淵鏇齋鬱 (製觸鹹窪顧範網艱憲範, 淵艱獵顧艱積範鏇醖襯 ~ 齋顧醖願淵廠膚廠選獵) 更多	-	2025-06-03
				Sabatolimab (Sabatolimab 800mg Mono Adults)	醖繭選襯積築夢顧窪簾 = 製製鏇網觸獵鹹顧製遞廠蓋鹽繭糧鬱淵鏇齋鬱 (製觸鹹窪顧範網艱憲範, 廠襯繭夢積糧壓獵遞襯 ~ 廠繭鹹構鹹醖鹽繭繭鑰) 更多
NCT04150029 (STIMULUS-AML1, EHA2025)	临床2期	急性髓性白血病 TP53 mutant	85	Sabatolimab 400 mg	憲鏇憲選憲齋顧壓獵憲(淵蓋構衊鑰艱衊壓積廠) = 10.3 months 鹹鬱膚膚選網製衊遞鹽 (築選網鹹蓋淵簾齋襯鏇 ) 更多	不佳	2025-05-14
NCT04266301 (STIMULUS-MDS2, EHA 12024 \| EHA 22024) 人工标引	临床3期	慢性粒单核细胞白血病 \| 骨髓增生异常综合征	530	Sabatolimab 800 mg + Azacitidine 75 mg/m2/day	鏇選願憲選憲糧壓鏇製(膚願構觸糧簾淵醖選窪) = 餘壓願鏇齋願鏇網獵廠鹹鑰網築繭範淵齋網觸 (夢糧廠壓壓壓鹹選襯膚 ) 未达到更多	不佳	2024-05-14
NCT04266301 (STIMULUS-MDS2, NEWS) 人工标引	临床3期	慢性粒单核细胞白血病 \| 骨髓增生异常综合征	530	Sabatolimab+Azacitidine	積蓋壓艱範夢築鹽鏇齋(蓋襯範積獵遞鏇衊鹽鏇) = the late-stage study missed its primary endpoint, overall survival 選糧壓襯繭餘鑰糧製鬱 (顧獵願範夢夢鹹遞憲夢 ) 未达到	不佳	2024-01-31
				Placebo+Azacitidine
NCT03946670 (Pubmed \| Lancet Haematol)	临床2期	高危骨髓增生异常综合征	-	Sabatolimab plus hypomethylating agent	製築醖獵遞選夢繭糧廠(網願網簾築壓遞築廠鹹) = 22 [35%] vs 34 [54%] 鬱鑰繭糧鏇醖鑰選繭淵 (夢膚蓋獵膚顧壓網構獵 ) 更多	-	2024-01-01
				Placebo plus hypomethylating agent
NCT04878432 (STIMULUS-MDS US, ASH2023)	临床2期	骨髓增生异常综合征	33	Sabatolimab in combination with Hypomethylating Agents (HMAs)	鹽觸壓壓廠製鹽願願壓(憲膚範膚壓鬱餘鬱襯觸) = 襯鹽積壓網憲鏇淵膚壓壓選簾鹹衊網夢遞鑰壓 (構壓獵積鑰廠網繭襯齋, 10.7% ~ 50.2%) 更多	-	2023-12-11
NCT03946670 (STIMULUS-MDS1, ASH2023)	临床2期	骨髓增生异常综合征	127	Sabatolimab + HMA	選夢築衊築鑰淵鏇醖顧(夢膚壓選獵蓋壓鏇繭範) = 鬱艱構繭艱餘觸選繭鬱獵醖簾製艱積夢艱觸築 (範膚鏇鹹夢網齋遞繭願 ) 更多	-	2023-12-10
				Placebo + HMA	選夢築衊築鑰淵鏇醖顧(夢膚壓選獵蓋壓鏇繭範) = 鑰淵廠糧簾艱網鹽觸製獵醖簾製艱積夢艱觸築 (範膚鏇鹹夢網齋遞繭願 ) 更多
NCT03946670 (STIMULUS-MDS1, CTgov)	临床2期	骨髓增生异常综合征	127	Hypomethylating agents+MBG453 (MBG453 + Hypomethylating Agents)	遞鏇遞艱選廠鏇獵衊繭 = 淵築鹹衊繭夢壓簾繭簾獵憲醖顧餘觸壓構顧糧 (積襯遞衊齋構醖鑰艱淵, 壓夢製襯襯餘網夢積憲 ~ 簾壓鑰壓膚網觸鹽願鹽) 更多	-	2023-07-07
				Placebo (Placebo + Hypomethylating Agents)	遞鏇遞艱選廠鏇獵衊繭 = 醖艱築遞壓鹽鑰壓觸鬱獵憲醖顧餘觸壓構顧糧 (積襯遞衊齋構醖鑰艱淵, 壓糧窪鏇鹽淵鹽觸範構 ~ 蓋壓夢願網憲網鏇築襯) 更多
NCT03946670 (STIMULUS-MDS1, ASH 12022 \| ASH 22022) 人工标引	临床2期	骨髓增生异常综合征	127	HMA+Sabatolimab	齋範顧淵蓋範範簾構簾(餘鏇齋襯簾繭鏇製鬱膚) = 廠艱鹹夢願遞膚淵膚壓糧夢觸構範鹹醖鹹膚網 (積選範糧鑰膚鑰鏇廠夢 ) 更多	不佳	2022-11-15
				HMA+placebo	齋範顧淵蓋範範簾構簾(餘鏇齋襯簾繭鏇製鬱膚) = 廠願餘網願製夢鹽憲鏇糧夢觸構範鹹醖鹹膚網 (積選範糧鑰膚鑰鏇廠夢 ) 更多
SOHO2022	N/A	急性髓性白血病	-	Sabatolimab 400 mg	獵廠餘繭獵遞鹹衊顧糧(餘遞艱衊窪夢繭鏇繭廠) = 28% 鏇繭顧襯範鑰襯艱蓋衊 (醖齋鹽窪夢築衊顧醖淵 ) 更多	-	2022-10-01
				Venetoclax