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利用肿瘤微环境响应性双特异性纳米抗体-PROTAC靶向细胞内癌症蛋白以提高治疗效果。

Targeting intracellular cancer proteins with tumor-microenvironment-responsive bispecific nanobody-PROTACs for enhanced therapeutic efficacy.

作者信息

Deng Changping, Ma Jiacheng, Liu Yuping, Tong Xikui, Wang Lei, Dong Jiayi, Shi Ping, Wang Meiyan, Zheng Wenyun, Ma Xingyuan

机构信息

State Key Laboratory of Bioreactor Engineering East China University of Science and Technology Shanghai P. R. China.

Key Laboratory of Systems Biomedicine (Ministry of Education) Shanghai Center for Systems Biomedicine Shanghai Jiao Tong University Shanghai P. R. China.

出版信息

MedComm (2020). 2025 Jan 19;6(2):e70068. doi: 10.1002/mco2.70068. eCollection 2025 Feb.


DOI:10.1002/mco2.70068
PMID:39830023
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11742431/
Abstract

Proteolysis targeting chimeras (PROTACs) are pivotal in cancer therapy for their ability to degrade specific proteins. However, their non-specificity can lead to systemic toxicity due to protein degradation in normal cells. To address this, we have integrated a nanobody into the PROTACs framework and leveraged the tumor microenvironment to enhance drug specificity. In this study, we engineered BumPeD, a novel bispecific nanobody-targeted PROTACs-like platform, by fusing two nanobodies with a Furin protease cleavage site (RVRR) and a degron sequence (ALAPYIP or KIGLGRQKPPKATK), enabling the tumor microenvironment to direct the degradation of intracellular proteins. We utilized KN035 and Nb4A to target PD-L1 (programmed death ligand 1) on the cell surface and intracellular Survivin, respectively. In vitro experiments showed that BumPeD triggers Survivin degradation via the ubiquitin-proteasome pathway, inducing tumor apoptosis and suppressing bladder tumor cell proliferation and migration. In vivo experiments further confirmed BumPeD's robust anti-tumor efficacy, underscoring its potential as a precise protein degradation strategy for cancer therapy. Our platform provides a systematic approach to developing effective and practical protein degraders, offering a targeted theoretical basis and experimental support for the development of novel degradative drugs, as well as new directions for cancer therapy.

摘要

靶向蛋白降解嵌合体(PROTACs)因其降解特定蛋白质的能力而在癌症治疗中发挥着关键作用。然而,由于其非特异性,会导致正常细胞中的蛋白质降解,进而引发全身毒性。为了解决这一问题,我们将一个纳米抗体整合到PROTACs框架中,并利用肿瘤微环境来提高药物特异性。在本研究中,我们通过将两个纳米抗体与一个弗林蛋白酶切割位点(RVRR)和一个降解子序列(ALAPYIP或KIGLGRQKPPKATK)融合,构建了一个新型双特异性纳米抗体靶向的类PROTACs平台BumPeD,使肿瘤微环境能够指导细胞内蛋白质的降解。我们分别利用KN035和Nb4A靶向细胞表面的程序性死亡配体1(PD-L1)和细胞内的生存素。体外实验表明,BumPeD通过泛素-蛋白酶体途径触发生存素降解,诱导肿瘤细胞凋亡,并抑制膀胱肿瘤细胞的增殖和迁移。体内实验进一步证实了BumPeD强大的抗肿瘤疗效,突显了其作为一种精确的癌症治疗蛋白质降解策略的潜力。我们的平台为开发有效且实用的蛋白质降解剂提供了一种系统方法,为新型降解药物的开发提供了有针对性的理论基础和实验支持,也为癌症治疗提供了新方向。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f66a/11742431/08184cec630b/MCO2-6-e70068-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f66a/11742431/d344b5860f8c/MCO2-6-e70068-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f66a/11742431/7e6fb1e73185/MCO2-6-e70068-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f66a/11742431/4b7f64c2c6dc/MCO2-6-e70068-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f66a/11742431/7b97bcb0299e/MCO2-6-e70068-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f66a/11742431/2a83bf615a9b/MCO2-6-e70068-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f66a/11742431/6d10f36ef705/MCO2-6-e70068-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f66a/11742431/08184cec630b/MCO2-6-e70068-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f66a/11742431/d344b5860f8c/MCO2-6-e70068-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f66a/11742431/7e6fb1e73185/MCO2-6-e70068-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f66a/11742431/4b7f64c2c6dc/MCO2-6-e70068-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f66a/11742431/7b97bcb0299e/MCO2-6-e70068-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f66a/11742431/2a83bf615a9b/MCO2-6-e70068-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f66a/11742431/6d10f36ef705/MCO2-6-e70068-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f66a/11742431/08184cec630b/MCO2-6-e70068-g005.jpg

相似文献

[1]
Targeting intracellular cancer proteins with tumor-microenvironment-responsive bispecific nanobody-PROTACs for enhanced therapeutic efficacy.

MedComm (2020). 2025-1-19

[2]
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Angew Chem Int Ed Engl. 2025-1-27

[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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引用本文的文献

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Sci Rep. 2025-8-1

[2]
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[3]
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本文引用的文献

[1]
Split-Cas9-based targeted gene editing and nanobody-mediated proteolysis-targeting chimeras optogenetically coordinated regulation of Survivin to control the fate of cancer cells.

Clin Transl Med. 2023-8

[2]
UBE2S interacting with TRIM21 mediates the K11-linked ubiquitination of LPP to promote the lymphatic metastasis of bladder cancer.

Cell Death Dis. 2023-7-8

[3]
PROTACs: A novel strategy for cancer drug discovery and development.

MedComm (2020). 2023-5-29

[4]
Small molecule-nanobody conjugate induced proximity controls intracellular processes and modulates endogenous unligandable targets.

Nat Commun. 2023-3-24

[5]
Advances in antibody-based therapy in oncology.

Nat Cancer. 2023-2

[6]
ETV4 Mediated Tumor-Associated Neutrophil Infiltration Facilitates Lymphangiogenesis and Lymphatic Metastasis of Bladder Cancer.

Adv Sci (Weinh). 2023-4

[7]
A Cell-Permeant Nanobody-Based Degrader That Induces Fetal Hemoglobin.

ACS Cent Sci. 2022-12-28

[8]
Radiotherapy-Triggered Proteolysis Targeting Chimera Prodrug Activation in Tumors.

J Am Chem Soc. 2023-1-11

[9]
Antibody targeting of E3 ubiquitin ligases for receptor degradation.

Nature. 2022-10

[10]
Generation of a live attenuated influenza A vaccine by proteolysis targeting.

Nat Biotechnol. 2022-9

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