A Multicenter Open-label, Prospective Study to Evaluate the Efficacy and Safety of SIRT Using Yttrium-90 Glass Microspheres Followed by Durvalumab and Tremelimumab for Treatment of Hepatocellular Carcinoma With Portal Vein Thrombosis

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, being the third leading cause of cancer-related death worldwide, with approximately 745 000 deaths reported annually.
For advanced patients, including patients with tumoral portal vein thrombosis (PVT), most treatment guidelines recommend systemic therapy, either combination immunotherapy (IO) or combination of immunotherapy and anti-angiogenic treatment for first line option.
Results for PVT patients are provided in one trial with a median overall survival of 14.2 months with IO underlying the necessity to improve treatment of PVT patients. Two recent other phase 3 trials also reported positive results for different IO regimen.
Selective internal radiation therapy (SIRT) using yttrium-90 (90Y)-loaded glass microspheres (TheraSphereTM) can be used for patients with early stage to locally advanced HCC including PVT patients without extrahepatic spread (EHS). TheraSphereTM is recognized and is reimbursed in France for PVT patients without EHS, since 2019.Several retrospective studies have shown promising results for PVT patients.
Nowadays use of SIRT in locally advanced HCC is regaining interest based on the results of the randomized DOSISPHERE-01 study including non-operable patients, about 70% with PVT. This randomized Phase II trial using 90Y-loaded microspheres sought was noted the effectiveness of 90Y-loaded microspheres using a personalized dosimetry approach versus a standard dosimetry approach.
The use of a systemic treatment as IO after a locoregional treatment with the strong local debulking effect of SIRT is logical and of interest. Indeed, the most frequent pattern of progression after SIRT is recurrence in an untreated area, including untreated liver or EHS. Patients are then usually referred to IO.
Such kind of therapeutic approach, using SIRT followed by IO has already been evaluated in a phase 2 study using nivolumab after 90Y loaded resin microspheres with promising efficacy without safety deterioration.
The aim of this study is to evaluate SIRT followed by IO used according to their current indications in advanced HCC patient with PVT patients and without EHS.

开始日期2026-01-02

申办/合作机构

Center Eugene Marquis

[+1]

NCT06880523

/ Not yet recruiting临床2期IIT

A Phase II Study of STRIDE (Durvalumab + Tremelimumab) With Lenvatinib Versus STRIDE Alone in Patients With Unresectable Hepatocellular Carcinoma (SLIDE-HCC)

The purpose of this study is to compare the effects on participants' and liver cancer by adding a drug that is used on its own to treat this disease to a combination of two other drugs which is also used to treat liver cancer, compared to the two-drug combination alone.

开始日期2025-09-30

申办/合作机构

Canadian Cancer Trials Group

[+2]

NCT06855225

/ Not yet recruiting临床2期IIT

A Phase II Study of Single Tremelimumab With Regular Interval Durvalumab (STRIDE) Plus Gemcitabine and Cisplatin (GEMCIS) in Locally Advanced Unresectable/Metastatic Combined Hepatocellular-cholangiocarcinoma (cHCC-CCA)

This is a single arm phase 2 study of Single Tremelimumab with Regular Interval Durvalumab (STRIDE) plus Gemcitabine and Cisplatin (GEMCIS) in locally advanced unresectable/metastatic combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Cycles 1 through 8 will be in 3 week intervals and Cycles 9+ will be in 4 week intervals. Tremelimumab is administered at 300mg intravenously once at Cycle 1. Durvalumab is administered at 1500mg intravenously every 3 weeks for Cycles 1-8, then every 4 weeks for Cycles 9+. Gemcitabine is administered at 1000mg/m^2 intravenously on Day 1 and Day 8 of Cycles 1-8 only. Cisplatin is administered at 25mg/m^2 intravenously on Day 1 and Day 8 of Cycles 1-8 only. Subjects will require a visit with appropriate laboratory work prior to the start of each cycle. Disease assessment will occur at screening and then every 9 weeks until the end of Cycle 9. Disease assessments will then occur every 8 weeks. Subjects will continue treatment until progression per RECIST 1.1, toxicity or subject/physician decision. A maximum of 24 months treatment from Cycle 1 Day 1 is allowed.

开始日期2025-09-01

申办/合作机构

Hoosier Cancer Research Network

[+2]

100 项与曲美木单抗相关的临床结果

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100 项与曲美木单抗相关的转化医学

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100 项与曲美木单抗相关的专利（医药）

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662

项与曲美木单抗相关的文献（医药）

2025-12-31·mAbs

Engineered ipilimumab variants that bind human and mouse CTLA-4

Article

作者: Barman, Ishita ; Lee, Peter S. ; Diong, SJ ; Bee, Christine ; Rajpal, Arvind ; Kumar, Anusha ; West, Sean M. ; Chau, Bryant ; Strop, Pavel ; Robison, Brett ; Chang, Olin ; Korman, Alan J. ; Moon, Thomas M.

Testing of candidate monoclonal antibody therapeutics in preclinical models is an essential step in drug development. Identification of antibody therapeutic candidates that bind their human targets and cross-react to mouse orthologs is often challenging, especially for targets with low sequence homology. In such cases, surrogate antibodies that bind mouse orthologs must be used. The antibody 9D9, which binds mouse CTLA-4, is a commonly used surrogate for CTLA-4 checkpoint blockade studies in mouse cancer models. In this work, we reveal that 9D9 has significant biophysical dissimilarities to therapeutic CTLA-4 antibodies. The 9D9-mCTLA4 complex crystal structure was determined and shows that the surrogate antibody binds an epitope distinct from ipilimumab and tremelimumab. In addition, while ipilimumab has pH-independent binding to hCTLA-4, 9D9 loses binding to mCTLA-4 at physiologically relevant acidic pH ranges. We used phage and yeast display to engineer ipilimumab to bind mouse CTLA-4 with single-digit nM affinity from an initial state with no apparent binding. The engineered variants showed pH-independent and cross-reactive binding to both mouse and human CTLA-4. Crystal structures of a variant in complex with both mouse and human CTLA-4 confirmed that it targets an equivalent epitope as ipilimumab. These cross-reactive ipilimumab variants may facilitate improved translatability and future mechanism-of-action studies for anti-CTLA-4 targeting in murine models.

2025-12-01·Journal of Gastrointestinal Cancer

The Efficacy and Safety of Durvalumab and Tremelimumab with Concomitant Treatment for MSS/pMMR Metastatic Colorectal Cancer: A Single Arm Meta-Analysis

Article

作者: Zhang, Danning ; Chen, Tianyu

OBJECTIVES:

To address the issue that most microsatellite-stable (MSS) and proficient mismatch repair (pMMR) metastatic colorectal cancer (mCRC) patients have minimal response to immunotherapy, this meta-analysis evaluated the efficacy and safety of durvalumab and tremelimumab with concomitant treatment in treating MSS/pMMR metastatic colorectal cancer.

METHODS:

All included trials were prospective studies with a median patient age of 63 years, of which 94.2% were MSS/pMMR mCRC patients, with a male to female ratio of 1.5:1. Based on durvalumab and tremelimumab treatment, one study performed surgical resection on resectable cases, while the other four studies performed radiotherapy or chemotherapy on unresectable cases. Analyses include objective response rate (ORR).etc. for drug activity, overall survival (OS) and progression-free survival (PFS) for therapeutic efficacy, and adverse events (AEs) for safety. The risk of bias was assessed by sensitivity analysis.

RESULTS:

5 studies involving 228 patients were included in this meta-analysis. The pooled estimates showed a median OS of 9.26 months, median PFS of 2.53 months, partial response (PR) of 13.6%, stable disease (SD) of 32.8%, ORR of 12.5% and disease control rate (DCR) of 65.4%. AEs were generally low, with pruritus (27.5%), diarrhea (28.8%), and fatigue (53.9%) being the most common, while other AEs occurred at less frequencies.

CONCLUSIONS:

Durvalumab and tremelimumab with concomitant treatment for MSS/pMMR mCRC patients is relatively effective and safe, which is helpful in addressing the problem of mCRC with MSS/pMMR that has minimal response to immunotherapy.

2025-12-01·Journal of Gastrointestinal Cancer

Neutrophil-to-Lymphocyte Ratio (NLR) as a Predictive Biomarker in Advanced Hepatocellular Carcinoma Treated with First-Line Immunotherapy

Article

作者: Felismino, Tiago ; Martins, Luanna ; Brito, Angelo ; Maccali, Claudia ; Barroso, Matheus ; Carvalho, Daniela ; Coimbra, Felipe

PURPOSE:

Hepatocellular carcinoma (HCC) is a globally prevalent malignancy with high mortality and limited predictive biomarkers. The neutrophil-to-lymphocyte ratio (NLR), a systemic inflammation marker, has been proposed as a prognostic tool. This study aimed to evaluate the association between baseline NLR and clinical outcomes in patients with advanced HCC treated with first-line immunotherapy.

METHODS:

We conducted a retrospective analysis of 58 consecutive patients with advanced HCC treated with atezolizumab plus bevacizumab or durvalumab plus tremelimumab at a Latin American cancer center between July 2020 and March 2025. Baseline NLR was calculated from pretreatment blood counts and dichotomized using a cut-off of 4. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariable and multivariable Cox regression models were applied to assess prognostic and predictive factors. The association between NLR and disease control rate (DCR) was evaluated using logistic regression.

RESULTS:

Among 58 patients, 15 (28.8%) had NLR ≥ 4. Median PFS was significantly shorter in patients with NLR ≥ 4 compared to those with NLR < 4 (2.3 vs. 8.2 months; p < 0.001). In multivariable analysis, NLR ≥ 4 remained independently associated with inferior PFS (HR 3.90; 95% CI, 1.83-8.33; p < 0.001). NLR was not associated with OS. Patients with NLR ≥ 4 had markedly lower odds of achieving disease control (OR 0.04; 95% CI, 0.002-0.28; p = 0.005).

CONCLUSION:

Baseline NLR ≥ 4 is associated with inferior PFS and reduced DCR in patients with advanced HCC receiving immunotherapy. NLR may serve as a cost-effective predictive biomarker to inform immunotherapy strategy.

509

项与曲美木单抗相关的新闻（医药）

2025-08-13

·抗体圈

巨大预期差的潜力靶点

CTLA-4这个靶点可能有巨大的预期差。CTLA-4是最早被研究的免疫检查点之一，其相关单抗也是最早上市的免疫检查点相关单抗，要比PD-(L)1相关单抗早一些年头。但是随着BMS的Y药（伊匹木单抗）上市，这个靶点的单抗便沉寂了十余年之久，一直到阿斯利康的替西木单抗上市才打破了Y药独占该靶点十余年的局面。而随后，随着康方AK104火箭般速度上市，该靶点便早早进入了双抗时代。这个靶点远没有PD-1这么顺风顺水，也就是说在它身上还有比较大的预期差。在这个时代里，也许可以在双抗身上找一些该靶点的机会，但是，单抗时代里一些联用的经验教训，也有值得我们吸收借鉴的地方。我们看到其实在双抗甚至三抗的在研管线，CTLA-4有机会发光发热。 01 CTLA-4靶点本身与Y药 CTLA-4又称为CD152，是活化T细胞表面的一种受体。1987年，Brunet等人通过筛选小鼠溶细胞性T细胞衍生的cDNA文库发现了该受体。在免疫过程之中，我们之间曾经有写到过T细胞的活化依赖于TCR与APC的MHC呈递的特定抗原的结合。然而，这种识别，即第一个T细胞活化信号，不足以引起T细胞活化，要完全激活T细胞，需要第二个激活信号，也就是我们常说的共刺激信号。该信号由T 细胞的可诱导CD28受体提供，该受体与活化的专职APC上的配体B7结合。那么CTLA-4和这些又有什么关系呢？它与CD28是竞争关系，竞争结合APC上的B7，并且关于二者亲和力方面的研究表明，CTLA-4受体与B7配体（CD80/CD86）的结合亲和力更高，且表面密度更低，因此在与B7配体的结合方面胜过CD28受体。因此，在存在CTLA-4受体的情况下，如果缺乏二次活化信号，则会导致T细胞无法活化。此外，CTLA-4受体还被证实能将B7配体从APC表面隔离，导致其表面配体显著耗竭。（图源：Current understanding of CTLA-4: from mechanism to autoimmune diseases）从这个角度来说，对于癌症患者而言，显然CTLA-4越多，对于癌症患者免疫系统活化越不利，要想办法抑制CTLA-4发挥它的功效。于是，就诞生了CTLA-4相关的单抗。首先必须要提到的自然是CTLA-4单抗的首秀——伊匹木单抗。它由诺贝尔奖获得者James P. Allison发明，年代要追溯到上世纪九十年代（推荐一篇文章《Ipilimumab: A tale of twists and turns》），它的临床应用专利被授权给当时的一家小公司NeXstar Pharmaceuticals，后来辗转吉利德，Medarex（Medarex中间还与辉瑞签署过共同开发伊匹木单抗的协议），最后才来到BMS的手中（2009年BMS收购Medarex），在2011年该药物才修成正果获得FDA批准。临床试验中的过程也是一波三折。如果采用传统研发方式，即基于RECIST标准评估疗效，那么将会面临一个问题：由于T细胞浸润至肿瘤细胞，这在放射学检查中将会显示为肿瘤体积增大，根据RECIST 标准，这可被视为疾病进展，患者将无法继续参与试验。因此需要密切注视患者进展，直到能够评估无进展生存期为止。具体的三期临床参见文献《Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy》，患者接受III期皮肤黑色素瘤完全切除术后，我们将其随机分配接受伊匹木单抗（剂量为10 mg/kg，475例）或安慰剂（476例），每3周给药一次，共给药4次，之后每3个月给药一次，最长给药3年，或直至出现疾病复发或不可接受的毒性作用。无复发生存期为主要终点。临床最后结果上，伊匹木单抗组5年无复发生存率为40.8%，安慰剂组为30.3%；伊匹木单抗组5年总生存率为65.4%，安慰剂组为54.4%。（图源：《Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy》）伊匹木单抗的缘起，大致如此。 02 PD-1单抗的带动可以这么说，PD-1单抗，或者更确切的说是O药，给了伊匹木单抗新的生命。我们今天看伊匹木单抗获批的适应症，除了第一个适应症是单药之外，剩下的适应症全部是和O药联用的。疗效和安全性方面我们以最常见的癌症NSCLC进行对比，它的三期临床试验为CheckMate -227。正好该试验是一线治疗NSCLC，基本不用去对比患者基线。对于PD-L1表达水平≥1%的患者，纳武利尤单抗联合伊匹单抗治疗组的OS为17.1个月，化疗组为14.9个月，OS的HR为0.79，算是验证出了疗效。安全性如下表所示，在纳武利尤单抗联合伊匹木单抗治疗组和化疗组中，研究者确定与试验治疗相关的3级或4级不良事件的发生率相似（32.8% vs. 36.0%）。纳武利尤单抗联合伊匹木单抗治疗中，任何级别的治疗相关严重不良事件的发生率均高于化疗组（24.5% vs. 13.9%），导致停药的治疗相关不良事件的发生率也高于化疗组（18.1% vs. 9.1%）。如今有些文章提到两药联用导致的安全性问题，但其实这个安全性我们今天来看，3级、4级TRAE上和化疗的安全性差不了太多。但这个OS数据看起来却比较擦边，似乎获益不算特别显著。那么我们再对比K药的一线治疗NSCLC的OS数据，K药在TPS≥1的人群中，三期试验的中位OS为16.4个月，HR同样为0.79。似乎O药联合伊匹木单抗才能达到K药单药的效果，而K药现在常见的疗法是联合化疗。必须要和O药捆绑使用+OS获益并不算显著，或许是伊匹木单抗销售额一直不温不火的主要原因。2024年，它的销售额在25亿美元左右。或许在这之后的方向上，提高疗效仍然是一大重要问题。 03 新的可能性当然，现在到了双抗时代，一些伊匹木单抗刚刚上市或者还没上市的时候，CTLA-4的双抗便已经迫不及待在占领市场了。其中跑得最快的自然是康方的AK104。首先值得一提的是COMPASSION-15，AK104联合化疗一线治疗胃癌，AK104单抗+化疗组 vs 安慰剂+化疗组的中位PFS是7个月vs 5.3个月，中位OS是14.1个月vs 11.1个月，ORR是65.2% vs 48.9%，中位DOR是8.8个月vs 4.4个月。其中PFS和ORR的显著差异性自然肉眼可见，最为重要的是卡度尼利在OS上也做出了显著的差异性：HR达到了0.66，不再是之前HR在0.8左右徘徊的擦边状态。然后是COMPASSION-16，AK104联合化疗联合贝伐珠单抗对比化疗联合贝伐珠单抗一线治疗宫颈癌。在全人群中，加用卡度尼利单抗后，12月OS率从73.7%提高至83.1%，24月OS率从48.4%提高至62.6%，AK104可显著降低36%的死亡风险。HR再一次小于0.7。 AK104告诉了我们真正的好药应该是什么样子。之后的PD-(L)1×CTLA-4双抗和三抗还有好几条，这里就不一一列举了。并且有一个很重要的点，目前虽然PD-1×VEGF双抗BD交易炒的火热，但是PD-1×CTLA-4双抗却一直不温不火，康方自己在电话会中也表示不排除AK104借船出海的可能性，并且也欢迎合作伙伴去联系，这使得AK104出爆款交易成为了可能。当然，目前还只是可能的状态。目前我们去看这个双抗乃至三抗，绝大部分原因是拓展PD-1×VEGF双抗之外的可能性，从目前AK104的情况去看，该双抗是有非常大的潜力的。虽然伊匹木单抗不温不火，但是也许在CTLA-4双抗上能够杀出黑马也说不定。除了PD-1×CTLA-4双抗/三抗之外，还有一些biotech在伊匹木单抗的基础上开发新一代的单抗，这是另外的一大趋势。最为典型的是和铂医药的HBM4003，与已经上市的药物ipilimumab相比HBM4003具有以下优点：1）具有更小的分子量（76 kDa），因此具有更好的渗透性；2）通过Fc突变使抗体更强的ADCC效应，增强对Treg细胞的清除；3）较短的半衰期，减少药物的系统性的暴露时间，从而减少副作用；4）可以持续的清除Treg细胞，可以潜在的减少用药频率，减少副作用。除此之外，BioNTech也曾经买下了CTLA-4单抗——ONC-392，预付款达到2亿美金。结语：通过今天的资料搜集与拆解，笔者颠覆了以前的看法。以前笔者认为CTLA-4单抗不温不火主要是安全性导致的，现在看来主要还是市场竞争太激烈加上疗效上没有明显的优势所导致的。K药的疗效优势确实非常惊艳。而未来，就将让CTLA-4双抗们接棒了。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。

并购免疫疗法细胞疗法

2025-08-06

·药研网

双剑合璧: PD-1/CTLA-4 双抗开启免疫治疗2.0时代

自2011年全球首个CTLA-4单抗ipilimumab获批以来，免疫检查点抑制剂（ICIs）彻底改变了癌症治疗的格局。随着PD-1/PD-L1单抗的相继问世，免疫治疗逐步成为肿瘤临床实践的核心支柱。然而，单药治疗的局限性促使行业探索更高效的联合策略，PD-1/CTLA-4双抗应运而生，标志着免疫治疗迈入2.0时代。 2025年，中国在这一领域迎来爆发式进展：康方生物的卡度尼利单抗、齐鲁制药的QL1706等多款PD-1/CTLA-4双抗药物频频迎来利好，覆盖肺癌、肝癌、宫颈癌等十大癌种。这些突破不仅展现了中国创新药企的研发实力，更预示着双抗药物有望重塑肿瘤免疫治疗的未来格局。 CTLA-4与PD-1 细胞毒性T淋巴细胞相关抗原4 (CTLA-4) 和程序性死亡受体1 (PD-1) 免疫检查点是T细胞免疫功能的负调节因子。CTLA4单抗抑制这些靶点可增强免疫系统的活性，从而催生出针对黑色素瘤、非小细胞肺癌和其他癌症的新型免疫疗法。[1] CTLA-4 和 PD-1 在抑制免疫反应（包括抗肿瘤反应）方面的作用截然不同。 CTLA-4被认为在免疫反应早期（主要在淋巴结中）调节T细胞增殖，而PD-1则在免疫反应后期（主要在外周组织中）抑制T细胞。抑制这两个检查点的免疫肿瘤药物的临床特征可能因其机制差异而有所不同。这些差异不仅导致两种抑制剂在临床应用中表现出不同的疗效和毒性特征，更为其联合治疗策略提供了理论基础。深入理解这两个免疫检查点的分子机制，将有助于优化现有免疫治疗方案。 CTLA-4：免疫检查点抑制剂的“领导者” 细胞毒性T淋巴细胞相关蛋白4（ CTLA-4）是一种抑制性受体，属于CD28免疫球蛋白亚家族，主要由T细胞表达。其配体CD80和CD86通常位于抗原呈递细胞表面，可以与CD28或CTLA-4结合，分别产生共刺激或共抑制反应。[4] CTLA-4被认为是免疫检查点抑制剂的“领导者”，因为它主要在T细胞早期激活阶段起作用，竞争性地抑制与CD80/CD86的结合，从而抑制T细胞增殖。不同于PD1的“末端”免疫抑制，CTLA-4则是“中枢”调节分子，其作用位点在淋巴结，影响T细胞的初始激活与克隆扩增。[1] CTLA-4的这种作用机制使其在调节免疫反应、维持免疫平衡方面发挥着关键作用。基于CTLA-4的这一特性，研究人员开发了针对CTLA-4的药物靶点，旨在通过抑制CTLA-4的活性来增强T细胞的免疫应答，从而实现对肿瘤细胞的杀伤作用。就 CTLA4 单靶点而言，美国FDA（食品药品监督管理局）批准了2个CTLA-4单抗： 1) 百时美施贵宝（BMS）自主研发的伊匹木单抗（Ipilimumab，Yervoy）是全球首个获批的CTLA-4抑制剂，用于黑色素瘤、肾癌等适应症。 2) 由阿斯利康公司研发的替西木单抗（Tremelimumab，Imjudo）是一种全人源化IgG2单克隆抗体，近年来也相继获批用于肝癌和非小细胞肺癌（NSCLC）等适应症。本土创新药企也在加速布局CTLA-4领域。信达生物的IBI310（伊匹木单抗）是我国首个自主研发的CTLA-4单抗，目前已在中国提交上市申请。2025年2月22日，信达生物的信迪利单抗+伊匹木单抗双免联合治疗方案的上市申请获得国家药品监督管理局（NMPA）受理。随着PD-1/PD-L1抑制剂时代的到来，CTLA-4抑制剂主要以联用方式发挥作用（如伊匹木单抗+纳武利尤单抗）。 PD-1：解除“免疫刹车”的关键钥匙与仅限于 T 细胞的 CTLA-4 不同，PD-1 更广泛地表达于活化的 T 细胞、B 细胞和髓系细胞。 CTLA - 4在T细胞活化的启动期发挥作用，而 PD-1 在效应期发挥作用，主要在外周组织内。程序性细胞死亡蛋白1 (PD-1) ，也称为CD279，属于CD28超家族，通过调节T细胞活性、诱导抗原特异性T细胞凋亡以及抑制调节性T细胞凋亡，在抑制免疫反应和促进自身耐受方面发挥着至关重要的作用。 PD-1 配体的分布也不同于 CTLA-4 的配体。程序性细胞死亡配体1 (PD-L1) ,也叫CD274或B7-H1，属于B7家族,是一种跨膜蛋白，被认为是免疫反应的共抑制因子，它可以与PD-1结合，减少PD-1阳性细胞的增殖，抑制其细胞因子分泌并诱导细胞凋亡。PD-L1还在各种恶性肿瘤中发挥重要作用，它可以减弱宿主对肿瘤细胞的免疫反应。[2] PD-1/PD-L1轴抑制癌细胞内的T细胞活化、增殖和存活以及细胞毒性分泌[2] PD-1单抗（如nivolumab、pembrolizumab）通过阻断PD-1与PD-L1的结合，解除T细胞“刹车”，恢复其免疫杀伤活性。该机制在多种肿瘤类型中表现出持久而显著的疗效，尤其在非小细胞肺癌（NSCLC）、黑色素瘤、胃癌等中显示出优越的客观缓解率和生存延长效果。癌症中的 PD-1/PD-L1 抑制剂[2] 目前多种PD-1/PD-L1阻断mAbs已获批用于免疫治疗，对多种癌症有效。表1 已上市的靶向PD-1/PD-L1的单克隆抗体然而，PD-1单抗的作用主要集中在外周肿瘤微环境（TME）中，激活已“进入战场”的T细胞，对免疫原性较弱或免疫冷肿瘤（cold tumor）患者人群疗效受限，耐药问题也逐渐显现。吉满生物深耕CTLA-4/PD-1靶点领域，围绕细胞系、抗体及蛋白产品，打造覆盖靶点药物研发全流程的系统化解决方案，为抗体药物的筛选、功能验证及一致性评价提供高质量关键工具，全力助推企业加速从研发到临床申报的进程。详情咨询吉满客服联系同微信：18916119826！ PD-1/CTLA-4双抗不仅仅是“二合一” 以PD-1单抗和CTLA-4单抗为代表的免疫治疗改变了肿瘤治疗格局，但是单免治疗仍未能满足临床需求[5] 。PD-1单抗联合CTLA-4单抗提高了疗效，但也加剧了副作用[6,7]。为此，PD-1/CTLA-4双特异性抗体（BsAb）应运而生，为双免疫检查点阻断治疗提供了新的选择。双抗通过单一分子实现对PD-1和CTLA-4的同时阻断，设计上可通过工程手段优化空间结构和亲和力，实现肿瘤部位的精准聚集，从而增强抗肿瘤免疫活性、降低系统性毒性。此外，一些双抗还设计成更易于制造与注射的形式，如双价或四价结构，具备更好的生物分布与药代特性。从临床角度来看，PD-1/CTLA-4双抗有望通过机制协同和给药优化，在疗效与安全性之间取得更优平衡，是当前肿瘤免疫治疗的重要方向之一。 CTLA-4 和 PD-1 通路阻断全球PD-1/CTLA-4双抗研发进展一览目前全球范围内，已有多款PD-1/CTLA-4双抗进入临床开发阶段，如MGD019、QL1706和MEDI5752等，但仅有几款进入关键III期临床试验阶段。卡度尼利单抗（开坦尼） Cadonilimab（AK104）是由中国先声药业和康方生物联合开发的全球首款肿瘤免疫双抗，已在国内获批宫颈癌（二线、三线）疗法和胃癌一线疗法，正在推进胃癌、肝癌、NSCLC等多个III期适应症。 Cadonilimab采用独特的四价结构，具有低FcR亲和力设计，从而降低免疫相关毒性。其在胃癌III期研究中展现出优异的生存获益，尤其在PD-L1低表达亚组中同样有效，打破传统免疫单抗对PD-L1依赖的限制。 2025 年 1 月 1 日起，正式纳入医保；2025年6月，国家药监局（NMPA）批准卡度尼利单抗联合含铂化疗±贝伐珠单抗用于持续性、复发性或转移性宫颈癌的一线治疗。 QL1706 （Iparomlimab）艾帕洛利托沃瑞利单抗是由齐鲁制药有限公司自主研发的全球首个PD-1/CTLA-4双功能组合抗体药物。2024年9月30日，获NMPA附条件批准上市，用于既往接受含铂化疗治疗失败的复发或转移性宫颈癌患者的治疗。 Volrustomig（MEDI572）阿斯利康开发的一种新型 PD-1/CTLA-4 双特异性抗体，可优先结合 PD-1 阳性、活化T 细胞中的 CTLA-4，能介导 PD-1 的内吞和降解来抑制 PD-1 靶点。[8] KN046 KN046 是一款靶向PD-1/CTLA-4的新型双特异性抗体，该药物对 PD-L1 具有更高的亲和力，并能介导肿瘤微环境中调节性 T 细胞的耗竭[9]。其 I 期试验显示，KN046 单药治疗标准治疗失败的晚期实体瘤患者，ORR 为 12.5%[10]。总结与展望从PD-1和CTLA-4的单独应用，到双抗策略的诞生与临床实践，免疫治疗正朝着更精准、更高效、更安全的方向演进。PD-1/CTLA-4双抗不仅体现了分子设计上的创新，也可能成为下一代免疫治疗的关键基石。如果说PD-1开启了免疫治疗的黄金时代，PD-1/CTLA-4双抗或许正是打开“深层治愈”之门的新钥匙。吉满生物吉满生物深耕CTLA-4/PD-1靶点领域，围绕细胞系、抗体及蛋白产品，打造覆盖靶点药物研发全流程的系统化解决方案，为抗体药物的筛选、功能验证及一致性评价提供高质量关键工具，全力助推企业加速从研发到临床申报的进程。今年我们还成功获得了HEK293、Jurkat E6.1、CHO-K1 等细胞商业使用授权，提供全面的溯源文件，赋能合作伙伴从临床前开发到IND/BLA 阶段进行合规研究，帮助客户规避法律风险并加速商业化进程。 PD1-PDL1产品列表 CTLA-4产品列表细胞系数据展示👍 GM-C26486：H_CTLA4 PD-1 Reporter Cell Line 使用 Anti-CTLA-4/PD-1 hIgG1 Antibody(Cadonilimab) 验证结果吉满生物的GM-C26486报告基因细胞系已在多种应用场景下完成了验证，包括针对单抗、单抗联用和双抗等不同场景的功能评估。实验结果表明，该细胞系能够高效支持CTLA-4&PD-1双抗药效的评价，为药物的筛选和机制研究提供了有力工具。细胞传代数据展示 GM-C09097 H_PDCD1(PD-1) CHO-K1 Cell Line 使用Pembrolizumab流式验证细胞传代至少25代以后，表达仍然稳定蛋白产品ELISA验证数据（部分） GM-87593RP Human PD1 Protein; His Tag 优异活性，信号强、背景低，批次间稳定性出色非常适合用于免疫检查点研究、抗体筛选及结合分析等实验 GM-87593RP Human PD1 Protein; His Tag GM-85609RP Human PDL1 Protein; His Tag 联系我们吉满生物(Genomeditech)成立于2011年，是专业从事生物科技服务和前沿技术研发的高新技术企业。吉满生物专注为生物药开发赋能，自主创立了国内知名的细胞系品牌-DDXCELL，目前已布局近400个热门靶向药靶点，超1000株现货单克隆细胞系，涵盖GPCR、细胞因子、免疫检查点、TAA等多领域，做到进口细胞的国产替代。此外，吉满生物还可在药物研发进程中提供一系列抗体、蛋白产品，旨在为客户提供高效的研发工具和解决方案! 扫码咨询扫码找现货参考资料 [1] Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am J Clin Oncol. 2016 Feb;39(1):98-106. doi: 10.1097/COC.0000000000000239. PMID: 26558876; PMCID: PMC4892769. [2] Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020 Mar 1;10(3):727-742. PMID: 32266087; PMCID: PMC7136921. [3] https://doi-org.libproxy1.nus.edu.sg/10.15252/embj.2022111556 [4] Van Coillie S, Wiernicki B, Xu J. Molecular and Cellular Functions of CTLA-4. Adv Exp Med Biol. 2020;1248:7-32. doi: 10.1007/978-981-15-3266-5_2. PMID: 32185705. [5] Zhang T, Lin Y, Gao Q. Bispecific antibodies targeting immunomodulatory checkpoints for cancer therapy. Cancer Biol Med. 2023;20(3):181–95. [6]Larkin J, Chiarion-Sileni V, Gonzalez R,et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(1):23-34. [7]Wu K, Yi M, Qin S,et al. The efficacy and safety of combination of PD-1 and CTLA-4 inhibitors: a meta-analysis. Exp Hematol Oncol. 2019;8:26. [8]https://mp.weixin.qq.com/s/oKizCBlEGDrH1B4755XHFQ [9] Jiang C, Zhang L, Xu X, et al. Engineering a smart agent for enhanced immunotherapy effect by simultaneously blocking PD-L1 and CTLA-4. Adv Sci (Weinh). 2021 Oct;8(20):e2102500. [10 ] Ma Y, Xue J, Zhao Y, Zhang Y, Huang Y, Yang Y, Fang W, Guo Y, Li Q, Ge X, Sun J, Zhang B, Zhang Y, Xiao J, Zhang L, Zhao H. Phase I trial of KN046, a novel bispecific antibody targeting PD-L1 and CTLA-4 in patients with advanced solid tumors. J Immunother Cancer. 2023 Jun;11(6):e006654.

免疫疗法

2025-08-06

·PMLiVE

AstraZeneca’s Imfinzi/Imjudo regimen recommended by NICE to treat liver cancer

AstraZeneca (AZ) has announced that Imfinzi (durvalumab) in combination with Imjudo (tremelimumab) has been recommended by the National Institute for Health and Care Excellence (NICE) to treat certain cases of liver cancer. The health technology assessment agency has recommended in final draft guidance that the ‘STRIDE’ regimen (single tremelimumab regular interval durvalumab) be used on the NHS in England and Wales as a first-line treatment for adults with advanced or unresectable hepatocellular carcinoma (HCC). This marks the first approval by NICE of a dual immunotherapy for liver cancer, AZ outlined. Approximately 6,600 people are diagnosed with liver cancer every year in the UK, with HCC accounting for more than 75% of all primary liver cancers cases. Around 70% of patients are diagnosed at an advanced stage, at which point treatment options are limited and prognosis is poor. NICE’s decision on STRIDE was supported by results from the late-stage HIMALAYA study, in which AZ’s regimen was associated with a statistically significant improvement in overall survival compared to the previous standard-of-care treatment, sorafenib, a tyrosine-kinase inhibitor. Median overall survival for STRIDE was 16.4 months versus 13.8 months for sorafenib, while 49% and 31% of STRIDE-treated patients were alive at 18 and 36 months, respectively, compared to 42% and 20% for sorafenib. Tom Keith Roach, president of AstraZeneca UK, said: “This is a positive step forward for people with advanced liver cancer and the first time this kind of immunotherapy combination will be available for these patients, showing a significant improvement in the number of patients living for five years or longer.” Also welcoming the recommendation, Vanessa Hebditch, director of policy and communications at the British Liver Trust, said: “Liver cancer incidence is rising rapidly, and patients often face limited treatment choices… This decision by NICE brings an important new treatment option to patients with advanced liver cancer.” The announcement comes just three months after AZ’s AKT inhibitor Truqap (capivasertib) was recommended by NICE as part of a combination treatment for advanced breast cancer. The company also received two separate recommendations from the agency in January for the use Imfinzi and Tagrisso (osimertinib) in lung cancer.

免疫疗法临床结果上市批准

100 项与曲美木单抗相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D06657	曲美木单抗	-	DB11771

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
肝细胞癌	加拿大	AstraZeneca Canada, Inc.	2023-08-31
晚期肝细胞癌	欧盟	AstraZeneca AB	2023-02-20
晚期肝细胞癌	冰岛	AstraZeneca AB	2023-02-20
晚期肝细胞癌	列支敦士登	AstraZeneca AB	2023-02-20
晚期肝细胞癌	挪威	AstraZeneca AB	2023-02-20
转移性非小细胞肺癌	欧盟	AstraZeneca AB	2023-02-20
转移性非小细胞肺癌	冰岛	AstraZeneca AB	2023-02-20
转移性非小细胞肺癌	列支敦士登	AstraZeneca AB	2023-02-20
转移性非小细胞肺癌	挪威	AstraZeneca AB	2023-02-20
晚期非小细胞肺癌	日本	AstraZeneca KK	2022-12-23
非小细胞肺癌	美国	AstraZeneca AB	2022-11-10
不可切除的肝细胞癌	美国	AstraZeneca AB	2022-10-21

未上市

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适应症	最高研发状态	国家/地区	公司	日期
非肌层浸润性膀胱肿瘤	临床3期	美国	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	日本	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	阿根廷	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	奥地利	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	巴西	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	加拿大	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	智利	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	法国	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	德国	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	希腊	AstraZeneca PLC	2021-08-05

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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


NCT03638141 (CTgov)	临床2期	肝细胞癌	21	Tremelimumab+Durvalumab	窪鏇窪齋遞襯廠膚衊範 = 淵範餘衊顧窪蓋範鹹糧顧簾艱網齋壓積鬱糧構 (鹹夢網製繭壓選壓蓋網, 鑰願鹹糧廠膚壓憲壓簾 ~ 鹹鬱積餘鹹艱築獵積觸) 更多	-	2025-08-17
NCT03518606 (MOVIE, Pubmed \| Breast)	临床2期	晚期乳腺癌 ER Negative \| PR Negative \| HER2 Negative	30	Tremelimumab plus Durvalumab combined to metronomic oral Vinorelbine	夢衊鹽襯繭獵遞鬱鑰夢(鹽窪築衊壓夢鹹鹽繭憲) = 顧鬱網顧糧築製糧獵蓋鏇糧鑰憲範築衊積遞鬱 (選鑰餘繭鹽鹽遞鏇獵糧, 5.5 ~ 29.8) 更多	不佳	2025-08-01
NCT03703297 (ADRIATIC, CTgov)	临床3期	局限期小细胞肺癌	730	Durvalumab (Durvalumab)	膚膚繭網網夢鑰壓鹹醖(餘膚積淵選顧廠築艱鬱) = 艱繭鏇糧廠膚艱獵壓繭構築衊繭網窪衊網糧窪 (觸鹹顧鏇製鹽願餘鹹襯, 鬱餘顧艱憲夢鏇鏇醖糧 ~ 衊廠鹽窪鏇壓顧鑰膚壓) 更多	-	2025-08-01
				placebo (Placebo)	膚膚繭網網夢鑰壓鹹醖(餘膚積淵選顧廠築艱鬱) = 製窪選鹽襯顧顧鹽壓鑰構築衊繭網窪衊網糧窪 (觸鹹顧鏇製鹽願餘鹹襯, 遞獵製觸廠齋廠簾積蓋 ~ 衊淵廠獵構觸夢壓願淵) 更多
HIMALAYA Trial (ESMO_GI2025)	N/A	-	233	Durvalumab+Tremelimumab	繭繭鏇築淵艱製構選構(觸構窪積齋積鬱繭壓窪) = 鹽鑰鏇淵鏇顧範簾衊艱鬱積繭齋遞獵廠鬱醖膚 (廠鹽鏇鏇糧選築壓齋範, 43.2 ~ 73.9) 更多	积极	2025-07-03
				Durvalumab	遞餘壓顧獵壓憲襯鏇襯(憲鏇壓壓網簾膚淵衊糧) = 糧憲醖壓膚簾製夢淵襯鏇遞壓餘鹽願積獵蓋衊 (鹽簾鹽蓋齋鹽壓鏇鏇艱, 8.0 ~ NR) 更多
NCT02815995 (CTgov)	临床2期	卡波西肉瘤 \| 晚期肉瘤	57	Tremelimumab+Durvalumab (Adipocytic Tumors Group)	夢製齋簾憲簾網範鬱網 = 製齋簾鏇選簾壓廠鏇觸網蓋衊衊鏇廠夢選鏇簾 (鑰窪齋簾壓製齋壓範蓋, 餘蓋襯製繭構壓餘鬱餘 ~ 蓋憲壓鏇膚膚獵觸簾遞) 更多	-	2025-06-12
				Tremelimumab+Durvalumab (Vascular Tumors Group)	夢製齋簾憲簾網範鬱網 = 糧餘遞窪艱淵觸製艱積網蓋衊衊鏇廠夢選鏇簾 (鑰窪齋簾壓製齋壓範蓋, 淵鑰艱獵憲夢選遞膚構 ~ 願觸遞餘範願憲壓淵糧) 更多
NCT02821754 (2019-002767-98, Pubmed \| Gut)	临床2期	肝细胞癌 interferon responses \| antigen presentation \| ICOS ... 更多	28	Tremelimumab plus Durvalumab	願醖鹽膚鬱襯淵醖艱鑰(淵選窪鬱醖夢膚窪獵淵) = 蓋糧築廠網獵膚構鹹窪襯鏇範憲艱獵遞膚艱鏇 (網醖壓艱繭窪餘蓋艱顧 )	-	2025-06-01
NCT05844046 (AIO-MONTBLANC, ASCO2025)	临床2期	不可切除的肝细胞癌一线 Child-Pugh A \| AFP ≥400 ng/mL	70	Durvalumab + Tremelimumab	網選廠製膚顧積窪衊獵(壓廠積蓋繭製願蓋鏇淵) = 襯鹽鹹淵餘窪鑰醖窪淵蓋壓顧鏇醖鑰蓋醖餘顧 (鏇獵構網艱齋顧遞鹹艱 ) 更多	积极	2025-05-30
ACTRN12617001325392 (BCT1703 DIAmOND, ESMO_BC 12025 \| ESMO_BC 22025) 人工标引	临床2期	晚期 HER2 阳性乳腺癌	68	Total	鬱繭齋願鹹窪齋構齋築(繭膚網窪範鏇衊糧糧獵) = 選艱積構膚齋鏇繭顧積蓋齋憲築淵範鹽選艱廠 (膚廠餘繭糧製繭淵餘糧 ) 更多	积极	2025-05-16
				tremelimumabtremelimumab 75mg with durvalumab 1500mg Q4Wdurvalumab 1500mg Q4W and Trastuzumab 2mg/kg Q1W for 12 weeks with ongoing Q3W durvalumab 1120mgTrastuzumab 2mg/kg Q1W for 12 weeks with ongoing Q3W durvalumab 1120mg and Trastuzumab 6mg/kg (C1, estrogen receptor (ER)-positive (≥1%))	鬱繭齋願鹹窪齋構齋築(繭膚網窪範鏇衊糧糧獵) = 夢鹹鹽齋蓋遞憲鹹簾鹽蓋齋憲築淵範鹽選艱廠 (膚廠餘繭糧製繭淵餘糧 ) 更多
NCT03164616 (POSEIDON, ESMO_ELCC2025)	临床3期	转移性非小细胞肺癌一线 EGFR/ALK wild-type	175	Durvalumab + Tremelimumab + Chemotherapy	築網鑰襯糧壓選廠選簾(鹽網廠鬱願鹽獵鏇鬱製) = D+T+CT demonstrated statistically significant improvements in both progression-free survival (PFS; HR 0.72; 95% CI 0.60-0.86; p = 0.0003) and overall survival (OS; HR 0.77; 95% CI 0.65-0.92; p = 0.0030) vs CT alone, leading to approvals for this regimen. D+CT significantly improved PFS vs CT (0.74; 95% CI 0.62-0.89; p = 0.0009), with a positive trend for OS improvement (HR 0.86; 95% CI 0.72-1.02; p = 0.0758) 壓齋構艱窪壓窪餘糧醖 (糧艱繭蓋獵積網簾壓鏇 ) 更多	积极	2025-03-26
				Durvalumab + Chemotherapy
NCT02879162 (CTgov)	临床2期	晚期癌症	140	Tremelimumab+Durvalumab	艱獵窪觸繭觸窪餘餘齋(遞襯糧範鹹鑰積鏇選襯) = 鑰夢積壓艱獵壓網窪製範餘築觸鹽鏇壓衊積鬱 (顧餘繭遞鏇製鬱餘積範, 艱願艱製鑰鏇構獵蓋糧 ~ 鏇壓衊窪遞製艱鹽醖襯) 更多	-	2025-02-17