• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

AGEN1884，一种新型人源 IgG1 抗 CTLA-4 抗体的毒理学和药理学评估。

Toxicological and pharmacological assessment of AGEN1884, a novel human IgG1 anti-CTLA-4 antibody.

机构信息

Immuno-modulatory Drug Discovery, Agenus Incorporated, Lexington, Massachusetts, United States of America.

Research Biochemistry, Agenus Incorporated, Lexington, Massachusetts, United States of America.

出版信息

PLoS One. 2018 Apr 4;13(4):e0191926. doi: 10.1371/journal.pone.0191926. eCollection 2018.

DOI:10.1371/journal.pone.0191926
PMID:29617360
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5884502/
Abstract

CTLA-4 and CD28 exemplify a co-inhibitory and co-stimulatory signaling axis that dynamically sculpts the interaction of antigen-specific T cells with antigen-presenting cells. Anti-CTLA-4 antibodies enhance tumor-specific immunity through a variety of mechanisms including: blockade of CD80 or CD86 binding to CTLA-4, repressing regulatory T cell function and selective elimination of intratumoral regulatory T cells via an Fcγ receptor-dependent mechanism. AGEN1884 is a novel IgG1 antibody targeting CTLA-4. It potently enhanced antigen-specific T cell responsiveness that could be potentiated in combination with other immunomodulatory antibodies. AGEN1884 was well-tolerated in non-human primates and enhanced vaccine-mediated antigen-specific immunity. AGEN1884 combined effectively with PD-1 blockade to elicit a T cell proliferative response in the periphery. Interestingly, an IgG2 variant of AGEN1884 revealed distinct functional differences that may have implications for optimal dosing regimens in patients. Taken together, the pharmacological properties of AGEN1884 support its clinical investigation as a single therapeutic and combination agent.

摘要

CTLA-4 和 CD28 是协同抑制和协同刺激信号轴的代表，它们动态地塑造了抗原特异性 T 细胞与抗原呈递细胞的相互作用。抗 CTLA-4 抗体通过多种机制增强肿瘤特异性免疫，包括：阻断 CD80 或 CD86 与 CTLA-4 的结合，抑制调节性 T 细胞功能，以及通过 Fcγ 受体依赖性机制选择性消除肿瘤内调节性 T 细胞。AGEN1884 是一种针对 CTLA-4 的新型 IgG1 抗体。它强烈增强了抗原特异性 T 细胞的反应性，与其他免疫调节抗体联合使用时可增强这种反应性。AGEN1884 在非人类灵长类动物中具有良好的耐受性，并增强了疫苗介导的抗原特异性免疫。AGEN1884 与 PD-1 阻断联合有效地在周围引发 T 细胞增殖反应。有趣的是，AGEN1884 的 IgG2 变体显示出明显的功能差异，这可能对患者的最佳剂量方案有影响。综上所述，AGEN1884 的药理学特性支持其作为单一治疗剂和联合用药进行临床研究。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f67c/5884502/bcc4385d5fc5/pone.0191926.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f67c/5884502/225fbc5f0c47/pone.0191926.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f67c/5884502/abfaf0b33d2f/pone.0191926.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f67c/5884502/967fa7590343/pone.0191926.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f67c/5884502/8257f04b072e/pone.0191926.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f67c/5884502/b46717b5fec7/pone.0191926.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f67c/5884502/669f4ec146c0/pone.0191926.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f67c/5884502/bcc4385d5fc5/pone.0191926.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f67c/5884502/225fbc5f0c47/pone.0191926.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f67c/5884502/abfaf0b33d2f/pone.0191926.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f67c/5884502/967fa7590343/pone.0191926.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f67c/5884502/8257f04b072e/pone.0191926.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f67c/5884502/b46717b5fec7/pone.0191926.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f67c/5884502/669f4ec146c0/pone.0191926.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f67c/5884502/bcc4385d5fc5/pone.0191926.g007.jpg

相似文献

1
Toxicological and pharmacological assessment of AGEN1884, a novel human IgG1 anti-CTLA-4 antibody.AGEN1884，一种新型人源 IgG1 抗 CTLA-4 抗体的毒理学和药理学评估。
PLoS One. 2018 Apr 4;13(4):e0191926. doi: 10.1371/journal.pone.0191926. eCollection 2018.
2
Combined immunotherapy: CTLA-4 blockade potentiates anti-tumor response induced by transcutaneous immunization.联合免疫疗法：CTLA-4 阻断增强经皮免疫诱导的抗肿瘤反应。
J Dermatol Sci. 2017 Sep;87(3):300-306. doi: 10.1016/j.jdermsci.2017.06.013. Epub 2017 Jun 16.
3
Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells.IgG2a 同种型的抗 CTLA-4 抗体通过减少肿瘤内调节性 T 细胞增强抗肿瘤活性。
Cancer Immunol Res. 2013 Jul;1(1):32-42. doi: 10.1158/2326-6066.CIR-13-0013. Epub 2013 Apr 7.
4
Differential control of human Treg and effector T cells in tumor immunity by Fc-engineered anti-CTLA-4 antibody.通过 Fc 工程化抗 CTLA-4 抗体对肿瘤免疫中的人 Treg 和效应 T 细胞进行差异化控制。
Proc Natl Acad Sci U S A. 2019 Jan 8;116(2):609-618. doi: 10.1073/pnas.1812186116. Epub 2018 Dec 26.
5
The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation.CTLA-4 x OX40 双特异性抗体 ATOR-1015 通过肿瘤定向免疫激活诱导抗肿瘤作用。
J Immunother Cancer. 2019 Apr 11;7(1):103. doi: 10.1186/s40425-019-0570-8.
6
Breaking immune tolerance by targeting CD25+ regulatory T cells is essential for the anti-tumor effect of the CTLA-4 blockade in an HLA-DR transgenic mouse model of prostate cancer.通过靶向 CD25+调节性 T 细胞来打破免疫耐受对于 CTLA-4 阻断在 HLA-DR 转基因前列腺癌小鼠模型中的抗肿瘤作用至关重要。
Prostate. 2014 Oct;74(14):1423-32. doi: 10.1002/pros.22858. Epub 2014 Aug 11.
7
Poxvirus-based active immunotherapy synergizes with CTLA-4 blockade to increase survival in a murine tumor model by improving the magnitude and quality of cytotoxic T cells.基于痘病毒的主动免疫疗法与CTLA-4阻断协同作用，通过提高细胞毒性T细胞的数量和质量来提高小鼠肿瘤模型的生存率。
Cancer Immunol Immunother. 2016 May;65(5):537-49. doi: 10.1007/s00262-016-1816-7. Epub 2016 Mar 10.
8
Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy.劫持抗体诱导的 CTLA-4 溶酶体降解以实现更安全、更有效的癌症免疫治疗。
Cell Res. 2019 Aug;29(8):609-627. doi: 10.1038/s41422-019-0184-1. Epub 2019 Jul 2.
9
A transendocytosis model of CTLA-4 function predicts its suppressive behavior on regulatory T cells.CTLA-4功能的转胞吞作用模型预测了其对调节性T细胞的抑制行为。
J Immunol. 2015 Mar 1;194(5):2148-59. doi: 10.4049/jimmunol.1401876. Epub 2015 Jan 28.
10
Anti-CD28 has a potent adjuvant effect on the antibody response to soluble antigens mediated through CTLA-4 by-pass.抗CD28对通过CTLA-4旁路介导的可溶性抗原抗体反应具有强大的佐剂作用。
Eur J Immunol. 2003 Jan;33(1):135-42. doi: 10.1002/immu.200390016.

引用本文的文献

1
Botensilimab, an Fc-Enhanced Anti-CTLA-4 Antibody, Is Effective against Tumors Poorly Responsive to Conventional Immunotherapy.博滕西利单抗，一种Fc增强型抗CTLA-4抗体，对传统免疫疗法反应不佳的肿瘤有效。
Cancer Discov. 2024 Dec 2;14(12):2407-2429. doi: 10.1158/2159-8290.CD-24-0190.
2
TG6050, an oncolytic vaccinia virus encoding interleukin-12 and anti-CTLA-4 antibody, favors tumor regression via profound immune remodeling of the tumor microenvironment.TG6050，一种编码白细胞介素-12 和抗 CTLA-4 抗体的溶瘤痘病毒，通过对肿瘤微环境的深刻免疫重塑促进肿瘤消退。
J Immunother Cancer. 2024 Jul 25;12(7):e009302. doi: 10.1136/jitc-2024-009302.
3

本文引用的文献

1
T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition.T细胞共刺激受体CD28是PD-1介导抑制作用的主要靶点。
Science. 2017 Mar 31;355(6332):1428-1433. doi: 10.1126/science.aaf1292. Epub 2017 Mar 9.
2
Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study.纳武利尤单抗联合伊匹木单抗作为晚期非小细胞肺癌的一线治疗方案（CheckMate 012）：一项开放标签的1期多队列研究结果
Lancet Oncol. 2017 Jan;18(1):31-41. doi: 10.1016/S1470-2045(16)30624-6. Epub 2016 Dec 5.
3
Superantigens hyperinduce inflammatory cytokines by enhancing the B7-2/CD28 costimulatory receptor interaction.
Diffuse intrinsic pontine glioma (DIPG): A review of current and emerging treatment strategies.
弥漫性脑桥内生型胶质瘤（DIPG）：当前及新兴治疗策略综述
Cancer Lett. 2024 May 28;590:216876. doi: 10.1016/j.canlet.2024.216876. Epub 2024 Apr 10.
4
Antitumor effect of plant-produced anti-CTLA-4 monoclonal antibody in a murine model of colon cancer.植物产生的抗CTLA-4单克隆抗体在结肠癌小鼠模型中的抗肿瘤作用。
Front Plant Sci. 2023 Aug 29;14:1149455. doi: 10.3389/fpls.2023.1149455. eCollection 2023.
5
Monoclonal antibodies in cervical malignancy-related HPV.宫颈癌相关人乳头瘤病毒中的单克隆抗体。
Front Oncol. 2022 Oct 6;12:904790. doi: 10.3389/fonc.2022.904790. eCollection 2022.
6
The foundations of immune checkpoint blockade and the ipilimumab approval decennial.免疫检查点阻断的基础和伊匹单抗批准的十年。
Nat Rev Drug Discov. 2022 Jul;21(7):509-528. doi: 10.1038/s41573-021-00345-8. Epub 2021 Dec 22.
7
Dual PD-1 and CTLA-4 Checkpoint Blockade Using Balstilimab and Zalifrelimab Combination as Second-Line Treatment for Advanced Cervical Cancer: An Open-Label Phase II Study.巴替利单抗和泽利鲁单抗联合双 PD-1 和 CTLA-4 检查点阻断作为晚期宫颈癌二线治疗的开放标签 II 期研究。
J Clin Oncol. 2022 Mar 1;40(7):762-771. doi: 10.1200/JCO.21.02067. Epub 2021 Dec 21.
8
Fc-Engineering for Modulated Effector Functions-Improving Antibodies for Cancer Treatment.用于调节效应功能的Fc工程——改进用于癌症治疗的抗体
Antibodies (Basel). 2020 Nov 17;9(4):64. doi: 10.3390/antib9040064.
9
Isolation of Two Novel Human Anti-CTLA-4 mAbs with Intriguing Biological Properties on Tumor and NK Cells.分离出两种对肿瘤细胞和自然杀伤细胞具有有趣生物学特性的新型人抗CTLA-4单克隆抗体。
Cancers (Basel). 2020 Aug 6;12(8):2204. doi: 10.3390/cancers12082204.
10
Ipilimumab and Its Derived EGFR Aptamer-Based Conjugate Induce Efficient NK Cell Activation against Cancer Cells.伊匹单抗及其基于表皮生长因子受体适配体的衍生缀合物可有效诱导自然杀伤细胞激活以对抗癌细胞。
Cancers (Basel). 2020 Feb 1;12(2):331. doi: 10.3390/cancers12020331.
超抗原通过增强B7-2/CD28共刺激受体相互作用来过度诱导炎性细胞因子。
Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):E6437-E6446. doi: 10.1073/pnas.1603321113. Epub 2016 Oct 5.
4
OX40, PD-1 and CTLA-4 are selectively expressed on tumor-infiltrating T cells in head and neck cancer.OX40、PD-1 和 CTLA-4 选择性地表现在头颈部癌症中的肿瘤浸润性 T 细胞上。
Clin Transl Immunology. 2016 Apr 15;5(4):e70. doi: 10.1038/cti.2016.16. eCollection 2016 Apr.
5
Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination.抗 CTLA-4 和抗 PD-1 抗体单药及联合治疗的安全性特征。
Nat Rev Clin Oncol. 2016 Aug;13(8):473-86. doi: 10.1038/nrclinonc.2016.58. Epub 2016 May 4.
6
Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study.度伐利尤单抗联合曲美木单抗治疗非小细胞肺癌的安全性和抗肿瘤活性：一项多中心1b期研究
Lancet Oncol. 2016 Mar;17(3):299-308. doi: 10.1016/S1470-2045(15)00544-6. Epub 2016 Feb 6.
7
CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition.CTLA-4与PD-1通路：它们抑制作用的相似性、差异及意义
Am J Clin Oncol. 2016 Feb;39(1):98-106. doi: 10.1097/COC.0000000000000239.
8
Beyond CTLA-4 and PD-1, the Generation Z of Negative Checkpoint Regulators.除了CTLA-4和PD-1之外，新一代负性检查点调节因子。
Front Immunol. 2015 Aug 21;6:418. doi: 10.3389/fimmu.2015.00418. eCollection 2015.
9
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.纳武利尤单抗与伊匹木单抗联合用药或单药治疗初治黑色素瘤
N Engl J Med. 2015 Jul 2;373(1):23-34. doi: 10.1056/NEJMoa1504030. Epub 2015 May 31.
10
Cytokine release assays for the prediction of therapeutic mAb safety in first-in man trials--Whole blood cytokine release assays are poorly predictive for TGN1412 cytokine storm.在首次人体试验中用于预测治疗性单克隆抗体安全性的细胞因子释放试验——全血细胞因子释放试验对TGN1412细胞因子风暴的预测性较差。
J Immunol Methods. 2015 Sep;424:43-52. doi: 10.1016/j.jim.2015.04.020. Epub 2015 May 7.