This is a single-arm pilot feasibility study evaluating the combination of Botensilimab and Balstilimab with Radiation Therapy (RT) in Non-Microsatellite Instability High (MSI-H) or Proficient Mismatch Repair (pMMR) chemorefractory colorectal cancer (CRC) with liver metastasis.

开始日期2026-01-01

申办/合作机构

The Massachusetts General Hospital

[+1]

NCT06346197

/ Not yet recruiting临床3期IIT

A Multicenter, Randomised, Comparative, Open-label Phase III Aiming to Compare the Survival of Patients With Locally Advanced or Metastatic MSI/dMMR Esogastric Adenocarcinomas Treated by a Combination of Immune Checkpoint Inhibitors (Botensilimab + Balstilimab) Versus the Standard of Care (FOLFOX/XELOX + Nivolumab)

CIME is a multicenter, randomised, comparative, open-label phase III study aiming to compare the survival of patients suffering from MSI-H/dMMR locally advanced or metastatic oeasogastric adenocarcinoma treated by a bi-immunotherapy (experimental arm) versus standard current treatment (FOLFOX/XELOX + nivolumab : standard arm).

开始日期2025-12-15

申办/合作机构

Centre Léon Bérard Lyon et Rhône-Alpes

[+1]

NCT07152821

/ Not yet recruiting临床3期IIT

Botensilimab + Balstilimab vs Best Supportive Care as Therapy in Chemo-refractory, Unresectable, Colorectal Adenocarcinoma: The BATTMAN Trial

This study is being done to answer the main question of: Do patients with colorectal cancer that cannot be removed by surgery, that is treated with two new immunotherapy drugs, botensilimab and balstilimab, live longer? Other important questions include: Is their quality of life better? Do their tumours slow in growth or possibly shrink in size? Are there markers in their tumour or blood that can predict whether they achieve any of these benefits? In addition, the study is done to confirm the safety of these immunotherapy drugs and to determine how long it takes for the body to metabolize them.

开始日期2025-11-30

申办/合作机构

Canadian Cancer Trials Group

[+2]

100 项与 Botensilimab 相关的临床结果

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100 项与 Botensilimab 相关的转化医学

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100 项与 Botensilimab 相关的专利（医药）

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518

项与 Botensilimab 相关的文献（医药）

2026-05-01·BIOMATERIALS

Glycolysis-inhibiting tumor cell-derived microparticles to enhance immunogenic cell death for synergistic cancer immunotherapy

Article

作者: Zhang, Miya ; Chen, Xiaoyuan ; Ma, Muye ; Ee, Pui Lai Rachel ; Tang, Wei ; Ding, Linwen ; Yang, Zhijuan ; Xu, Jian ; Yu, Guocan ; Han, Huize

In situ vaccination represents a promising cancer immunotherapy strategy, yet its efficacy in solid tumors remains limited, primarily due to the immunosuppressive tumor microenvironment (TME) and resistance to immunogenic cell death (ICD)-inducing anti-tumor treatments. Abnormal tumor metabolism, characterized by the "Warburg effect", shifts cancer cells toward glycolysis, leading to the production of immunosuppressive metabolites that hinder immune responses and comprise immunotherapy. Glycolysis inhibition has emerged as an effective strategy to overcome these challenges. In this study, we developed a combinatory therapeutic approach that co-delivers doxorubicin (DOX), a chemotherapeutic agent, and GSK2837808A (GSK), a glycolysis inhibitor, through tumor cell-derived microparticles (TMPs). The TMP platform facilitated targeted drug delivery and deep tumor penetration. The resulting formulation, TMP@DOX/GSK, effectively inhibited glycolysis, thereby enhancing tumor cell killing, promoting ICD, and amplifying immune responses. Notably, when combined with anti-CTLA-4 antibody, TMP@DOX/GSK completely eradicated melanoma in mice, prevented recurrence, and established long-term immune responses. Overall, this study demonstrates that integrating glycolysis inhibition with chemotherapy via TMP-based delivery systems can effectively overcome drug resistance, modulate the TME, and significantly improve the efficacy of anti-tumor immunotherapy.

2025-11-01·Clinical Gastroenterology and Hepatology

Efficacy and Safety of Budesonide Orodispersible Tablets for Eosinophilic Esophagitis up to 3 Years: An Open-Label Extension Study

Article

作者: Bredenoord, Albert Jan ; Biedermann, Luc ; Schlag, Christoph ; Pfurr, Sabrina ; Straumann, Alex ; Miehlke, Stephan ; Schoepfer, Alain M ; Attwood, Stephen ; Schubert, Stefan ; Madisch, Ahmed ; Hayat, Jamal ; von Arnim, Ulrike ; Santander, Cecilio ; Hruz, Petr ; Halstead, Mike ; Ciriza de Los Rios, Constanza ; Vieth, Michael ; Lucendo, Alfredo J ; Schmöcker, Christoph ; Mueller, Ralph

BACKGROUND & AIMS:

Budesonide orodispersible tablets (BOT) have been shown to be safe and effective in phase III double-blind trials of induction and 48-week maintenance therapy of eosinophilic esophagitis (EoE). We now analyzed the long-term efficacy and safety of BOT in a 96-week open-label extension (OLE) study.

METHODS:

All patients with EoE in the 48-week double-blind maintenance study were eligible to receive BOT treatment for up to 96 weeks. Dosage was 0.5 or 1.0 mg BOT, twice daily, at investigator's discretion. Clinical, histologic, endoscopic, quality of life, and safety measures were assessed.

RESULTS:

A total of 186 patients participated in the OLE up to 96 weeks. At week 96, 81.9% of patients had clinical remission, defined as an EoE Symptom Activity Index (EEsAI) score of ≤20 vs 77.7% at OLE baseline. A further 80.1% of patients were in histologic remission, defined as peak eosinophils per high-power field of <5, at week 96 vs 91.8% at OLE baseline. Mean EoE endoscopic reference scores (EREFS) were 1 at all time points measured. Mean EoE Quality of Life (EoE-QoL-A) Scale scores improved from 3.3 at OLE baseline to 3.5 at week 96. No new safety concerns were observed across 96 weeks of treatment. Suspected symptomatic candidiasis occurred at similar rates to prior BOT studies and was predominantly mild and resolved with treatment.

CONCLUSIONS:

Clinical and histologic remission of EoE could be maintained with BOT in a large majority of patients for up to 96 weeks, and for up to 144 weeks in patients with uninterrupted BOT therapy across all trials. No additional safety concerns were identified with long-term BOT treatment (ClinicalTrials.gov, Number: NCT02493335).

2025-11-01·LUNG CANCER

Immune checkpoint inhibitor-induced interstitial lung disease with and without CTLA-4 regimen in non-small cell lung cancer patients and PD-L1 < 1 %: A multicenter, retrospective study

Article

作者: Ota, Takayo ; Nomizo, Takashi ; Imabayashi, Tatsuya ; Hamai, Kosuke ; Azuma, Koichi ; Tamura, Yosuke ; Tanimura, Keiko ; Nishii, Yuuya ; Hibino, Makoto ; Iwanaga, Kentaro ; Yoshimine, Kohei ; Sumi, Toshiyuki ; Murata, Daiki ; Yamada, Tadaaki ; Ito, Kazuhiro ; Murotani, Kenta ; Okada, Asuka ; Takaki, Ryuichiro ; Takayama, Koichi ; Chibana, Kenji ; Oba, Tomohiro ; Goto, Yasuhiro ; Nakao, Akira ; Nishioka, Naoya ; Kaneda, Hiroyasu ; Yamada, Kazuhiko

BACKGROUND:

For patients with advanced or recurrent non-small cell lung cancer (NSCLC) and PD-L1 < 1 %, a combination of an anti-CTLA-4 and anti-PD-1 antibody with and without platinum-based chemotherapy are used as a first-line treatment. Although the combined use of anti-CTLA-4 antibody has favorable therapeutic efficacy, increased incidence and severity of immune-related adverse events, including immune checkpoint inhibitor-induced interstitial lung disease (ICI-ILD), remains a challenge.

METHODS:

A multicenter retrospective study of patients with advanced or recurrent NSCLC and PD-L1 < 1 % who received immune checkpoint inhibitors as a first-line treatment. The primary and secondary endpoints were incidence and prognostic impact, respectively, of ICI-ILD.

RESULTS:

The cohort included 376 patients, with 119 and 257 receiving a CTLA-4 regimen and non-CTLA-4 regimen, respectively. The ICI-ILD incidence tended to be higher in patients treated with the CTLA-4 regimen, but the difference from the non-CTLA-4 regimen was not significant. Patients with ICI-ILD treated with the CTLA-4 regimen tended to have longer progression-free survival and overall survival than those who received non-CLTLA-4 treatment, but the difference was not significant.

CONCLUSION:

For patients with NSCLC and PD-L1 < 1 %, the incidence of ICI-ILD tended to be higher in CTLA-4 regimens, and survival of patients with ICI-ILD tended to be longer for CTLA-4 regimens than for non-CTLA-4 regimens. Although the incidence of ICI-ILD in patients given CTLA-4 regimens tended to be higher than in those given non-CTLA-4 regimens, development of ICI-ILD does not necessarily negatively impact survival.

192

项与 Botensilimab 相关的新闻（医药）

2025-11-18

·雪球

免疫治疗后PD-1时代

转自©氨基观察-创新药组原创出品作者|沙晓威免疫治疗进入“后PD-1时代”，迭代与突破正成为主旋律。当众多创新靶点尚在验证途中，BioNTech正选择将目光重新投向CTLA-4这一老靶点身上。作为全球首个问世的免疫检查点抑制剂，CTLA-4抑制剂高开低走后沉寂许久。在最新研发日中，BioNTech则将新一代CTLA-4单抗Gotistobart纳入优先免疫调节管线，沉寂多年的CTLA-4再度回归行业视野。凭借分子设计的双重创新，Gotistobart在早期临床中展现出增效减毒的潜力，提高了安全性窗口与持续疗效，为PD-1耐药患者带来突破性希望。眼下，BioNTech把CTLA-4重新推到幕前，意在抢夺下一代IO的基石。创新总是有着矛盾而迷人的两面性，不到最后一刻，永远不能对一款药物下结论。那么，老靶点的新生，会成为下一代免疫治疗的破局关键吗？/01/老靶点的新生在免疫治疗的发展历程中，CTLA-4的发现早于PD-1，却走出了截然不同的发展轨迹。作为首个打开免疫治疗大门的靶点，CTLA-4单抗以全身免疫激活的机制开辟了全新治疗路径，但也因固有缺陷长期处于PD-1的光环之下。与PD-1单抗20余款产品上市盛况不同，截至目前，全球获批的CTLA-4单抗仅有两款，分别是百时美施贵宝的Ipilimumab（Y药）和阿斯利康的Tremelimumab。市场表现也与PD-1抑制剂相差悬殊：2024年，K药的全球销售额近300亿美元，而Y药的同期销售额仅为25.3亿美元，不足K药的十分之一，甚至一大部分的占比是基于与PD-1单抗Nivolumab联用的适应症。安全性问题是制约CTLA-4抗体发展的核心瓶颈之一。早期CTLA-4抗体的作用机制直接：通过无差别抑制削弱Tregs的免疫抑制作用，进而激活全身免疫反应。缺点就是无法区分肿瘤与正常组织中的Tregs，易引发严重的免疫相关不良反应（IrAEs）。疗效上的劣势则让CTLA-4彻底被PD-1掩盖。2014年，K药、O药相继上市，CTLA-4抗体在黑色素瘤、非小细胞肺癌（NSCLC）等核心适应症中表现逊色。以黑色素瘤为例，Y药治疗的客观缓解率（ORR）仅10%-15%，而K药的ORR可达30%-40%，部分亚型甚至能突破50%。即便是联合治疗场景，CTLA-4抗体也多处于“辅助地位”。比如Tremelimumab目前获批的适应症均为与O药联合治疗。尽管发展受限，CTLA-4的研究从未停滞，而是朝着精准化方向转型。BioNTech从OncoC4引进的新一代CTLA-4单抗Gotistobart正是这一转型思路的典型代表，其分子设计通过双重创新实现了对传统CTLA-4抗体的突破。一方面，借助pH敏感型抗体技术，Gotistobart与CTLA-4结合形成的复合物被细胞内吞后，会在溶酶体的酸性环境中发生解离，使CTLA-4蛋白能够重返细胞表面重新发挥作用，避免了传统抗体导致的CTLA-4内吞降解，大幅提升了药物的治疗窗口。另一方面，通过Fc段的工程化改造，Gotistobart能够更高效地招募免疫效应细胞，精准清除TME中的Tregs，同时减少对正常组织的影响。正如OncoC4所言，这种机制使Gotistobart具备了长期、重复给药的潜力，为持续控制肿瘤提供了可能。早期临床数据初步验证了其潜力：在针对ICI耐受的NSCLC患者开展的1/2期临床试验中，Gotistobart单药治疗的ORR达29.6%，DCR高达70.4%，这一结果对PD-1耐药人群具有突破性意义。基于此，今年10月，该药物获得NMPA授予的突破性疗法认定，用于治疗PD-1耐药的晚期NSCLC患者，成为首个在该适应症中获得突破性认定的新一代CTLA-4抗体。/02/BioNTech的IO双支柱将Gotistobart纳入优先免疫调节管线，是BioNTech构建下一代IO治疗体系的关键布局。在其优先免疫调节剂研发管线中，PD-L1/VEGF双抗Pumitamig与CTLA-4单抗Gotistobart构成两大核心支柱，分别代表了多靶点协同增效与老靶点升级改造的发展策略。作为BioNTech重点布局的下一代IO基石，Pumitamig的核心优势在于同时结合PD-L1与VEGF两个靶点，一方面阻断PD-1/PD-L1信号通路，激活效应T细胞的抗肿瘤功能，另一方面抑制VEGF介导的肿瘤血管生成，改善肿瘤微环境。目前，BioNTech已推动Pumitamig20项临床落地，除了小细胞癌、NSCLC和三阴性乳腺癌的三期临床，更是加速推进泛癌种布局以及与化疗、ADC、新型免疫靶点药物（如PVRIG抑制剂BNT3213）等不同且新颖的联合疗法研究。相比之下，尽管是首次进入BioNTech的重点研发项目名单，但从即将推进的研究布局来看，Gotistobart的定位绝非对现有IO药物的简单补位，而是要成为BioNTech下一代IO治疗的核心基石之一。BioNTech在研发日中明确提出，Gotistobart的研发目标是“探索新的组合以确定潜在的未来治疗标准”。Gotistobart的“魅力”在于循环利用的机制以及针对PD-1耐药人群的潜力，这为其开展多样化的联合治疗研究提供了基础。从研发日的报告上看，BioNTech计划围绕Gotistobart启动了覆盖多个癌种、多种联合模式的研究：开展单药治疗针对二线及以上鳞癌NSCLC患者的3期临床试验，明确单药治疗潜力；开展联合K药治疗宫颈癌的2期研究，以明确CTLA-4、PD-1的协同效应潜力；还有联合核药PLUVICTO治疗转移性去势抵抗性前列腺癌的早期研究；以及开展覆盖多种实体瘤的早期临床研究，进一步挖掘潜在肿瘤适应症。其中，与PLUVICTO联合治疗前列腺癌的研究极具看点。2025年ASCO大会公布的1期研究初步结果显示，该联合方案耐受性良好，且临床前模型已证实，放射治疗能够选择性扩增并激活肿瘤微环境中的Tregs，这恰好与Gotistobart的作用机制匹配此外，Gotistobart与mRNA疫苗BNT116的联合研究也已启动，借助mRNA疫苗引导T细胞向肿瘤抗原特异性分化的能力，结合Gotistobart清除免疫抑制细胞的作用，有望实现更持久的抗肿瘤免疫记忆。尽管Gotistobart目前还处于早期适应症扩张和验证阶段，但是BioNTech的双支柱策略已经清晰：Pumitamig通过多靶点协同作用提升免疫治疗疗效，覆盖广泛实体瘤治疗需求；Gotistobart目前则聚焦PD-1耐药以及肿瘤晚期等难治人群，两者构成了肿瘤全周期的免疫治疗。/03/CTLA-4值得期待Gotistobart的进展与BioNTech的战略布局只是CTLA-4赛道升温的一个缩影，全球药企正从分子设计优化、双抗研发、联合治疗等多个维度挖掘这一靶点的潜力。在单抗领域，Agenus公司的Botensilimab采用人源化Fc段增强设计，通过强化ADCC效应提升对肿瘤微环境中Tregs的清除效率，与ipilimumab相比，能同时激活先天与适应性免疫系统，尤甚至在冷肿瘤中表现潜力。其在与Balstilimab（PD-1抑制剂）联合治疗微卫星稳定型转移性结直肠癌患者的2期临床中，实现了42%的两年生存率，平均OS为20.9个月，而对于已经接受过4线或更多治疗的患者，BOT/BAL的联合治疗方案可以实现两年生存率43%，ORR为19%。国产药企在CTLA-4靶点的设计同样表现亮眼，比如和铂医药的HBM4003。作为一款全人源重链抗CTLA-4抗体，HBM4003仅有76kDa，小分子的优势，能够更高效穿透肿瘤组织，提升肿瘤微环境中的药物浓度，同时，其Fc段经过突变改造，显著增强ADCC活性，可精准清除高表达CTLA-4的肿瘤浸润Tregs。不久前公布的2期临床数据显示，在既往接受过多种治疗的MSS转移性结直肠癌患者中，每21天接受HBM4003联合替雷利珠单抗治疗的ORR达34.8%，DCR60.9%，mPFS为4.2个月，且87.5%的相关不良事件为1、2级，安全性表现优异。双抗成为CTLA-4靶点的另一重要研发方向。康方生物的AK104是一款CTLA-4/PD-1双抗，同时阻断两个免疫检查点，实现协同激活免疫的效应。尽管热度低于PD-1/VEGF双抗依沃西，但公司计划通过联合策略挖掘其价值，近期宣布AK104与依沃西联用治疗胰腺癌术后辅助治疗的1期临床已完成首例给药。阿斯利康的Volrustomig同样是针对PD-1/CTLA-4的双抗，目前正在在NSCLC领域的研究正开展头对头K药的3期临床eVOLVE-Lung02，进度与实力不容小觑。联合治疗则持续拓展着CTLA-4的应用边界。BMS的“Y药+O药”组合已在黑色素瘤、NSCLC、肾癌等多个癌种中获得FDA批准，涉及十余项适应症；Tremelimumab与O药的联合方案已获批用于NSCLC治疗，与O药+铂类化疗的三联方案则拓展至前列腺癌一线。信达生物的IBI310则是国内研发进度领先的CTLA-4抗体，其与PD-1抑制剂信迪利单抗的联合方案在今年2月被CDE纳入优先审批，适应症为可切除的微卫星高度不稳定型或错配修复缺陷型结直肠癌患者的新辅助治疗。此外，CTLA-4抗体与ADC、核药、小核酸等新型疗法的联合也是研究方向，BioNTech探索的Gotistobart与核药PLUVICTO的联合，不仅是适应症的拓展也是机制的补充，为靶点价值的挖掘开辟了更多可能。总之，CTLA-4凭借独特的免疫调节机制与持续迭代的药物研发，有望摆脱PD-1的阴影，与多靶点药物、新型疗法形成协同，构建下一代IO治疗的基石。尤其是当PD-1的耐药及不敏感问题成为免疫治疗的核心挑战之际，CTLA-4则提供了另一条免疫调节途径。尽管过程仍充满挫折和不确定性，但是创新药的发展，从来都是螺旋上升的。随着新技术、新机制的出现，以及更多临床数据的涌现，那些曾经被否定的药物，也有可能重新焕发新的光芒。老靶点的新生，值得期待。#创新药时代来临##创新药##锂电池板块回落，赣锋锂业大跌#$云顶新耀(01952)$$康方生物(09926)$$荣昌生物(09995)$

2025-11-18

·氨基观察

CTLA-4又坐上了牌桌

©氨基观察-创新药组原创出品作者 | 沙晓威免疫治疗进入“后PD-1时代”，迭代与突破正成为主旋律。当众多创新靶点尚在验证途中，BioNTech正选择将目光重新投向CTLA-4这一老靶点身上。作为全球首个问世的免疫检查点抑制剂，CTLA-4抑制剂高开低走后沉寂许久。在最新研发日中，BioNTech则将新一代CTLA-4单抗Gotistobart纳入优先免疫调节管线，沉寂多年的CTLA-4再度回归行业视野。凭借分子设计的双重创新，Gotistobart在早期临床中展现出增效减毒的潜力，提高了安全性窗口与持续疗效，为PD-1耐药患者带来突破性希望。眼下，BioNTech把CTLA-4重新推到幕前，意在抢夺下一代IO的基石。创新总是有着矛盾而迷人的两面性，不到最后一刻，永远不能对一款药物下结论。那么，老靶点的新生，会成为下一代免疫治疗的破局关键吗？ / 01 / 老靶点的新生在免疫治疗的发展历程中，CTLA-4的发现早于PD-1，却走出了截然不同的发展轨迹。作为首个打开免疫治疗大门的靶点，CTLA-4单抗以全身免疫激活的机制开辟了全新治疗路径，但也因固有缺陷长期处于PD-1的光环之下。与PD-1单抗20余款产品上市盛况不同，截至目前，全球获批的CTLA-4单抗仅有两款，分别是百时美施贵宝的Ipilimumab（Y药）和阿斯利康的Tremelimumab。市场表现也与 PD-1抑制剂相差悬殊：2024年，K药的全球销售额近300亿美元，而Y药的同期销售额仅为25.3亿美元，不足K药的十分之一，甚至一大部分的占比是基于与PD-1单抗Nivolumab联用的适应症。安全性问题是制约CTLA-4抗体发展的核心瓶颈之一。早期CTLA-4抗体的作用机制直接：通过无差别抑制削弱Tregs的免疫抑制作用，进而激活全身免疫反应。缺点就是无法区分肿瘤与正常组织中的Tregs，易引发严重的免疫相关不良反应（IrAEs）。疗效上的劣势则让CTLA-4彻底被PD-1掩盖。 2014年，K药、O药相继上市，CTLA-4抗体在黑色素瘤、非小细胞肺癌（NSCLC）等核心适应症中表现逊色。以黑色素瘤为例，Y药治疗的客观缓解率（ORR）仅10%-15%，而K药的ORR可达 30%-40%，部分亚型甚至能突破50%。即便是联合治疗场景，CTLA-4抗体也多处于“辅助地位”。比如Tremelimumab目前获批的适应症均为与O药联合治疗。尽管发展受限，CTLA-4的研究从未停滞，而是朝着精准化方向转型。BioNTech从OncoC4引进的新一代CTLA-4单抗Gotistobart正是这一转型思路的典型代表，其分子设计通过双重创新实现了对传统CTLA-4抗体的突破。一方面，借助pH敏感型抗体技术，Gotistobart与CTLA-4结合形成的复合物被细胞内吞后，会在溶酶体的酸性环境中发生解离，使CTLA-4蛋白能够重返细胞表面重新发挥作用，避免了传统抗体导致的CTLA-4内吞降解，大幅提升了药物的治疗窗口。另一方面，通过Fc段的工程化改造，Gotistobart能够更高效地招募免疫效应细胞，精准清除TME中的Tregs，同时减少对正常组织的影响。正如OncoC4所言，这种机制使Gotistobart具备了长期、重复给药的潜力，为持续控制肿瘤提供了可能。早期临床数据初步验证了其潜力：在针对ICI耐受的NSCLC患者开展的1/2期临床试验中，Gotistobart单药治疗的ORR达29.6%，DCR高达70.4%，这一结果对PD-1耐药人群具有突破性意义。基于此，今年10月，该药物获得NMPA授予的突破性疗法认定，用于治疗PD-1耐药的晚期NSCLC患者，成为首个在该适应症中获得突破性认定的新一代CTLA-4抗体。 / 02 / BioNTech的IO双支柱将Gotistobart纳入优先免疫调节管线，是 BioNTech构建下一代IO治疗体系的关键布局。在其优先免疫调节剂研发管线中，PD-L1/VEGF双抗Pumitamig与CTLA-4单抗Gotistobart构成两大核心支柱，分别代表了多靶点协同增效与老靶点升级改造的发展策略。作为BioNTech重点布局的下一代IO基石，Pumitamig的核心优势在于同时结合PD-L1与VEGF两个靶点，一方面阻断PD-1/PD-L1信号通路，激活效应T细胞的抗肿瘤功能，另一方面抑制VEGF介导的肿瘤血管生成，改善肿瘤微环境。目前，BioNTech已推动Pumitamig20项临床落地，除了小细胞癌、NSCLC和三阴性乳腺癌的三期临床，更是加速推进泛癌种布局以及与化疗、ADC、新型免疫靶点药物（如PVRIG抑制剂BNT3213）等不同且新颖的联合疗法研究。相比之下，尽管是首次进入BioNTech的重点研发项目名单，但从即将推进的研究布局来看，Gotistobart的定位绝非对现有IO药物的简单补位，而是要成为BioNTech下一代IO治疗的核心基石之一。 BioNTech在研发日中明确提出，Gotistobart的研发目标是“探索新的组合以确定潜在的未来治疗标准”。Gotistobart的“魅力”在于循环利用的机制以及针对PD-1耐药人群的潜力，这为其开展多样化的联合治疗研究提供了基础。从研发日的报告上看，BioNTech计划围绕Gotistobart启动了覆盖多个癌种、多种联合模式的研究：开展单药治疗针对二线及以上鳞癌NSCLC患者的3期临床试验，明确单药治疗潜力；开展联合K药治疗宫颈癌的2期研究，以明确CTLA-4、PD-1的协同效应潜力；还有联合核药PLUVICTO治疗转移性去势抵抗性前列腺癌的早期研究；以及开展覆盖多种实体瘤的早期临床研究，进一步挖掘潜在肿瘤适应症。其中，与PLUVICTO联合治疗前列腺癌的研究极具看点。2025年ASCO大会公布的1期研究初步结果显示，该联合方案耐受性良好，且临床前模型已证实，放射治疗能够选择性扩增并激活肿瘤微环境中的Tregs，这恰好与Gotistobart的作用机制匹配此外，Gotistobart与mRNA疫苗BNT116的联合研究也已启动，借助mRNA疫苗引导T细胞向肿瘤抗原特异性分化的能力，结合Gotistobart清除免疫抑制细胞的作用，有望实现更持久的抗肿瘤免疫记忆。尽管Gotistobart目前还处于早期适应症扩张和验证阶段，但是BioNTech的双支柱策略已经清晰：Pumitamig通过多靶点协同作用提升免疫治疗疗效，覆盖广泛实体瘤治疗需求；Gotistobart目前则聚焦PD-1耐药以及肿瘤晚期等难治人群，两者构成了肿瘤全周期的免疫治疗。 / 03 / CTLA-4值得期待 Gotistobart的进展与BioNTech的战略布局只是CTLA-4赛道升温的一个缩影，全球药企正从分子设计优化、双抗研发、联合治疗等多个维度挖掘这一靶点的潜力。在单抗领域，Agenus公司的Botensilimab采用人源化Fc段增强设计，通过强化ADCC效应提升对肿瘤微环境中Tregs的清除效率，与ipilimumab相比，能同时激活先天与适应性免疫系统，尤甚至在冷肿瘤中表现潜力。其在与Balstilimab（PD-1抑制剂）联合治疗微卫星稳定型转移性结直肠癌患者的2期临床中，实现了42%的两年生存率，平均OS为20.9个月，而对于已经接受过4线或更多治疗的患者，BOT/BAL的联合治疗方案可以实现两年生存率43%，ORR为19%。国产药企在CTLA-4靶点的设计同样表现亮眼，比如和铂医药的HBM4003。作为一款全人源重链抗CTLA-4抗体，HBM4003仅有76kDa，小分子的优势，能够更高效穿透肿瘤组织，提升肿瘤微环境中的药物浓度，同时，其Fc段经过突变改造，显著增强ADCC活性，可精准清除高表达CTLA-4的肿瘤浸润Tregs。不久前公布的2期临床数据显示，在既往接受过多种治疗的MSS转移性结直肠癌患者中，每21天接受HBM4003联合替雷利珠单抗治疗的ORR达34.8%，DCR 60.9%，mPFS为4.2个月，且87.5%的相关不良事件为1、2级，安全性表现优异。双抗成为CTLA-4靶点的另一重要研发方向。康方生物的AK104是一款CTLA-4/PD-1双抗，同时阻断两个免疫检查点，实现协同激活免疫的效应。尽管热度低于PD-1/VEGF双抗依沃西，但公司计划通过联合策略挖掘其价值，近期宣布AK104与依沃西联用治疗胰腺癌术后辅助治疗的1期临床已完成首例给药。阿斯利康的Volrustomig同样是针对PD-1/CTLA-4的双抗，目前正在在NSCLC领域的研究正开展头对头K药的3期临床eVOLVE-Lung02，进度与实力不容小觑。联合治疗则持续拓展着CTLA-4的应用边界。BMS的“Y药+O药”组合已在黑色素瘤、NSCLC、肾癌等多个癌种中获得FDA批准，涉及十余项适应症；Tremelimumab与O药的联合方案已获批用于NSCLC治疗，与O药+铂类化疗的三联方案则拓展至前列腺癌一线。信达生物的IBI310则是国内研发进度领先的CTLA-4抗体，其与PD-1抑制剂信迪利单抗的联合方案在今年2月被CDE纳入优先审批，适应症为可切除的微卫星高度不稳定型或错配修复缺陷型结直肠癌患者的新辅助治疗。此外，CTLA-4抗体与ADC、核药、小核酸等新型疗法的联合也是研究方向，BioNTech探索的Gotistobart与核药PLUVICTO的联合，不仅是适应症的拓展也是机制的补充，为靶点价值的挖掘开辟了更多可能。总之，CTLA-4凭借独特的免疫调节机制与持续迭代的药物研发，有望摆脱PD-1的阴影，与多靶点药物、新型疗法形成协同，构建下一代IO治疗的基石。尤其是当PD-1的耐药及不敏感问题成为免疫治疗的核心挑战之际，CTLA-4则提供了另一条免疫调节途径。尽管过程仍充满挫折和不确定性，但是创新药的发展，从来都是螺旋上升的。随着新技术、新机制的出现，以及更多临床数据的涌现，那些曾经被否定的药物，也有可能重新焕发新的光芒。老靶点的新生，值得期待。 PS：欢迎扫描下方二维码，添加氨基君微信号交流。

2025-11-06

·FierceBiotech

UroGen hands anti-CTLA-4 drug back to Agenus after being unimpressed with phase 1 data

\"UGN-301’s overall clinical profile did not meet UroGen’s internal benchmarks for advancement to phase 2,\" UroGen explained Thursday.\n UroGen is handing an anti-CTLA-4 antibody back to Agenus after concluding phase 1 data for the bladder cancer drug didn’t reach the benchmark for further development.New Jersey-based UroGen forked over $10 million in upfront cash for the license to the candidate, called zalifrelimab or UGN-301, back in 2019. At the time, the idea was to develop and ultimately commercialize zalifrelimab in combination with UroGen’s TLR7/8 agonist UGN-201 for the treatment of urinary tract cancers.The program was also an opportunity to test out RTGel, UroGen’s sustained-release, hydrogel-based tech designed to improve the therapeutic profiles of existing drugs.But, having now wrapped up a phase 1 dose-escalation study of zalifrelimab, it appears UroGen has lost confidence in the asset.“While the study confirmed proof of concept for RTGel as a viable platform for local delivery of complex immunotherapies, UGN-301’s overall clinical profile did not meet UroGen’s internal benchmarks for advancement to phase 2,” the company explained in its third-quarter earnings release this morning. As a result, UroGen has notified Agenus that it is terminating their license agreement. It means Agenus will miss out on the $115 million in clinical development and regulatory milestones and $85 million in commercial milestone paydays that could have come its way if zalifrelimab had achieved success.Anti-CTLA-4 checkpoint inhibitors have proven their worth in oncology in the form of Bristol Myers Squibb’s blockbuster Yervoy and AstraZeneca’s Imjudo.The decision by UroGen marks the latest rejection for Agenus after Bristol Myers Squibb axed a TIGIT bispecific antibody pact last year and then Incyte broke off an immuno-oncology deal in February. The Massachusetts-based biotech ended last year reorganizing after failing to gain traction with the FDA on its PD-1 candidate balstilimab.

临床1期引进/卖出免疫疗法抗体药物偶联物

100 项与 Botensilimab 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
晚期癌症	临床3期	法国	Agenus, Inc.	2025-12-15
肝转移	临床3期	法国	Agenus, Inc.	2025-12-15
转移性胃腺癌	临床3期	法国	Agenus, Inc.	2025-12-15
不能切除的大肠癌	临床3期	加拿大	Agenus, Inc.	2025-11-30
肛门肿瘤	临床3期	荷兰	Agenus, Inc.	2024-01-29
食管鳞状细胞癌	临床3期	荷兰	Agenus, Inc.	2024-01-29
MMRD实体瘤	临床3期	荷兰	Agenus, Inc.	2024-01-29
III期结肠癌	临床2期	美国	Agenus, Inc.	2025-11-07
微卫星稳定型直肠癌	临床2期	美国	Agenus, Inc.	2025-02-20
局部晚期直肠癌	临床2期	-	City of Hope National Medical Center	2024-11-01

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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


NCT03860272 (ESMO2025)	临床1期	晚期恶性实体瘤	343	Botensilimab + Balstilimab (IO naïve)	鑰襯窪範夢遞醖範壓遞(顧鏇積簾遞網鏇網艱鬱) = 淵鏇鹽網網淵構窪窪餘齋餘糧簾衊構構網鹹夢 (製膚夢壓憲醖願衊齋齋 ) 更多	积极	2025-10-17
				Botensilimab + Balstilimab (IO refractory)	鑰襯窪範夢遞醖範壓遞(顧鏇積簾遞網鏇網艱鬱) = 簾餘鹹簾襯顧簾選糧構齋餘糧簾衊構構網鹹夢 (製膚夢壓憲醖願衊齋齋 ) 更多
NCT03860272 (ESMO_GI2025)	临床1期	肝转移 \| 转移性微卫星稳定结直肠癌	123	Botensilimab 1 mg/kg + Balstilimab 3 mg/kg	鏇憲壓選願顧窪鬱獵醖(醖餘鑰窪鹹蓋醖廠積網) = 觸糧鏇鏇鏇獵鹹夢襯構廠選製醖憲蓋衊網遞憲 (鑰獵夢範構簾廠襯願鏇, 48 ~ 66) 更多	积极	2025-07-03
NCT05608044 (ASCO2025)	临床2期	转移性结直肠癌 pMMR	10	Botensilimab monotherapy	選齋範繭顧糧網遞簾簾(築積襯糧顧齋餘製廠願) = 壓衊醖襯觸鹹鑰廠遞蓋夢範淵淵齋顧蓋衊夢襯 (壓選顧鹽鹹齋艱獵襯醖 )	积极	2025-05-30
NCT03860272 (Phase 1 study of botensilimab and balstilimab, AACR2025)	临床1期	肝细胞癌	19	Botensilimab	製繭艱製齋襯獵選鬱膚(構構糧繭觸襯築網網願) = occurring in 37% of pts (16% G3) 鏇窪網繭壓繭製餘膚憲 (選壓鏇網艱顧衊齋夢糧 ) 更多	积极	2025-04-29
NCT03860272 (Pubmed \| J Clin Oncol) 人工标引	临床1期	肉瘤	64	Botensilimab + Balstilimab	廠範鏇獵網襯廠廠膚壓(獵鬱構鏇繭鑰網淵夢鏇) = The most common treatment-related adverse event (TRAE) was diarrhea/colitis occurring in 35.9% of patients, with grade 3 in 6.3% of patients. 鏇艱艱齋顧積範鹹膚衊 (廠鬱遞齋壓蓋憲壓壓醖 )	积极	2025-01-27
				Botensilimab + Balstilimab (angiosarcoma)
UNICORN (ASCO_GI2025)	临床2期	错配修复缺陷或微高卫星不稳定性结肠癌新辅助 pMMR \| dMMR	56	Botensilimab 1 mg/kg	糧選選襯齋夢鏇窪簾壓(築膚製繭醖醖餘憲鬱鑰) = 蓋顧衊鏇遞鏇窪築網糧積衊齋衊夢醖繭範壓廠 (繭廠壓積窪窪積遞願鹽 ) 更多	积极	2025-01-23
				Botensilimab 1 mg/kg + Balstilimab 3 mg/kg	餘積餘網鏇齋窪艱淵鬱(顧夢醖醖壓遞窪壓鬱鏇) = 觸構積簾積繭觸簾窪鹽鑰憲選餘顧鬱艱膚齋壓 (鬱網襯衊襯積憲壓餘齋 ) 更多
NCT05571293 (NEST, ASCO_GI2025)	临床2期	错配修复缺陷或微卫星高度不稳定性结直肠癌新辅助 pMMR \| dMMR \| MSI-H ... 更多	-	Neoadjuvant BOT 75 mg/m2	簾鏇襯淵製鏇鬱衊齋獵(鏇憲壓衊艱衊願衊衊蓋) = grade 2 diarrhea/colitis occurred in 8% 鑰範糧獵壓遞觸繭夢範 (窪築觸鹽膚顧壓廠鑰鏇 ) 更多	积极	2025-01-23
				Neoadjuvant BAL 240 mg/m2
NCT05608044 (ASCO_GI2025)	临床2期	转移性微卫星稳定结直肠癌 MSS \| pMMR \| KRAS mutant ... 更多	234	Botensilimab 75 mg Q6W	願蓋襯糧壓鏇夢顧範壓(構鏇積鏇願顧鑰網鬱顧) = 鬱襯衊繭襯製製繭網鬱糧築壓淵齋觸範簾醖網 (網醖襯齋鏇衊壓衊餘網 ) 更多	积极	2025-01-23
				Botensilimab 150 mg Q6W	願蓋襯糧壓鏇夢顧範壓(構鏇積鏇願顧鑰網鬱顧) = 鑰製鬱築襯顧範構淵繭糧築壓淵齋觸範簾醖網 (網醖襯齋鏇衊壓衊餘網 ) 更多
NCT05627635 (ASCO_GI2025)	临床1期	微卫星稳定型结直肠癌 MSS	14	Folinic acid, fluorouracil, oxaliplatin, bevacizumab, botensilimab, balstilimab (FOLFOX-3B)	簾齋窪鹽遞廠膚廠範壓(觸鑰築淵醖遞夢廠糧積) = one pt at DL1 with transient G3 AST/ALT elevation and transient G2 colitis (resolved with steroids and infliximab), one pt at DL1 with G2 hypothyroidism and one patient at DL2 with G2 hyperthyroidism 願築夢構壓繭顧夢憲範 (簾鑰觸糧網廠鏇範襯壓 ) 更多	积极	2025-01-23
NCT05864534 (Pubmed \| Neuro Oncol)	临床2期	胶质瘤	-	FcE-aCTLA-4	壓醖鹽廠繭積顧選網鹹(衊齋醖艱艱艱範糧觸顧) = 憲鬱網壓蓋簾製願鑰鹹廠鏇願鏇鑰壓壓餘餘醖 (範壓選艱齋鏇範鏇顧淵 )	-	2024-11-04