A next-generation anti-CTLA-4 probody mitigates toxicity and enhances anti-tumor immunity in mice.

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-10-10 DOI:10.1038/s41467-025-64081-y

Weian Cao,Junfan Chen,Yutong Fu,Haitao Jiang,Yu Gao,Huiming Huang,Yang-Xin Fu,Wenyan Wang

{"title":"A next-generation anti-CTLA-4 probody mitigates toxicity and enhances anti-tumor immunity in mice.","authors":"Weian Cao,Junfan Chen,Yutong Fu,Haitao Jiang,Yu Gao,Huiming Huang,Yang-Xin Fu,Wenyan Wang","doi":"10.1038/s41467-025-64081-y","DOIUrl":null,"url":null,"abstract":"CTLA-4 is a promising target for immune checkpoint inhibition in cancer therapy, with CTLA-4 blockade achieving prolonged overall survival for responding patients. However, the progressively elevated doses of anti-CTLA-4 agents, aimed at achieving better efficacy, result in increased toxicities, limiting their clinical applications. Here, we generate a prodrug design of the anti-CTLA-4 antibody, named ProCTLA-4, by folding the Fab fragment of the antibody in a tumor-associated protease-based manner. In preclinical mouse models, ProCTLA-4 effectively depletes suppressive regulatory T cells within the tumor microenvironment and enhances tumor-associated antigen-specific CD8+ T cell responses, while exhibiting reduced toxicity compared to currently available CTLA-4 blockade approaches. Furthermore, compared to the currently used Probody therapeutics for anti-CTLA-4 (BMS986288), ProCTLA-4 has more advantages in efficacy amplification, such as in poor immunogenic melanoma. Our design establishes an alternative paradigm for antibody agents that limits the emergence of immune-related adverse events (irAE) while increasing therapeutic efficacy.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"39 1","pages":"9029"},"PeriodicalIF":15.7000,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Communications","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41467-025-64081-y","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

CTLA-4 is a promising target for immune checkpoint inhibition in cancer therapy, with CTLA-4 blockade achieving prolonged overall survival for responding patients. However, the progressively elevated doses of anti-CTLA-4 agents, aimed at achieving better efficacy, result in increased toxicities, limiting their clinical applications. Here, we generate a prodrug design of the anti-CTLA-4 antibody, named ProCTLA-4, by folding the Fab fragment of the antibody in a tumor-associated protease-based manner. In preclinical mouse models, ProCTLA-4 effectively depletes suppressive regulatory T cells within the tumor microenvironment and enhances tumor-associated antigen-specific CD8+ T cell responses, while exhibiting reduced toxicity compared to currently available CTLA-4 blockade approaches. Furthermore, compared to the currently used Probody therapeutics for anti-CTLA-4 (BMS986288), ProCTLA-4 has more advantages in efficacy amplification, such as in poor immunogenic melanoma. Our design establishes an alternative paradigm for antibody agents that limits the emergence of immune-related adverse events (irAE) while increasing therapeutic efficacy.

查看原文本刊更多论文

新一代抗ctla -4抗体减轻小鼠毒性并增强抗肿瘤免疫。

CTLA-4是癌症治疗中免疫检查点抑制的一个有希望的靶点，CTLA-4阻断可延长应答患者的总生存期。然而，为了获得更好的疗效而逐渐增加抗ctla -4药物的剂量，导致毒性增加，限制了它们的临床应用。在这里，我们通过以肿瘤相关蛋白酶为基础的方式折叠抗体的Fab片段，生成抗ctla -4抗体的前药设计，命名为ProCTLA-4。在临床前小鼠模型中，procla -4有效地消耗肿瘤微环境中的抑制性调节性T细胞，增强肿瘤相关抗原特异性CD8+ T细胞反应，同时与目前可用的CTLA-4阻断方法相比，显示出更低的毒性。此外，与目前使用的抗ctla -4 Probody疗法（BMS986288）相比，ProCTLA-4在疗效放大方面更具优势，例如在免疫原性较差的黑色素瘤中。我们的设计为抗体制剂建立了一种替代范例，在提高治疗效果的同时限制了免疫相关不良事件（irAE）的出现。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.