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用于阻断人TRPM4通道的人源化抗体的开发及体外特性研究

Development and in vitro characterization of humanized antibodies for blocking human TRPM4 channel.

作者信息

Wei Shunhui, Poore Charlene Priscilla, Verma Ravi Kumar, Low See Wee, Chen Bo, Fan Hao, Liao Ping

机构信息

Calcium Signalling Laboratory, Department of Research, National Neuroscience Institute, Singapore, 308433, Singapore.

Bioinformatics Institute (BII), Agency for Science Technology and Research (A*STAR), Singapore, 138671, Singapore.

出版信息

Sci Rep. 2025 Jun 5;15(1):19769. doi: 10.1038/s41598-025-05256-x.

DOI:10.1038/s41598-025-05256-x
PMID:40473754
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12141489/
Abstract

Transient receptor potential melastatin 4 (TRPM4) channel, a monovalent cation channel, plays a crucial role in various neurological disorders. We previously showed that TRPM4 activity can be blocked by our antibodies: M4P, which targets rat TRPM4 and M4M, against a similar antigenic epitope of human TRPM4. M4P and M4M demonstrated efficacy in mitigating stroke reperfusion injury. To facilitate human application, M4M was humanized through CDR grafting, resulting in human IgG1 antibodies (Ab1-6). These antibodies were evaluated for their binding affinity, surface staining, stability, and functional inhibition of the human TRPM4 channel. Ab6 (renamed as M4H) was selected and inhibited TRPM4 currents in human brain microvascular endothelial cells under ATP depletion conditions. Importantly, Ab6 (M4H) suppressed ATP depletion-induced cell swelling, indicating its potential for managing vascular injury in ischemic brain diseases. Future studies on animal models could advance the development of novel therapies of neurological disorders with vascular injury.

摘要

瞬时受体电位褪黑素4（TRPM4）通道是一种单价阳离子通道，在各种神经系统疾病中起关键作用。我们之前表明，TRPM4的活性可被我们的抗体阻断：针对大鼠TRPM4的M4P和针对人TRPM4相似抗原表位的M4M。M4P和M4M在减轻中风再灌注损伤方面显示出疗效。为便于人类应用，通过互补决定区（CDR）移植对M4M进行人源化，得到人IgG1抗体（Ab1 - 6）。对这些抗体进行了结合亲和力、表面染色、稳定性以及对人TRPM4通道功能抑制的评估。选择了Ab6（重命名为M4H），其在ATP耗竭条件下抑制人脑微血管内皮细胞中的TRPM4电流。重要的是，Ab6（M4H）抑制了ATP耗竭诱导的细胞肿胀，表明其在管理缺血性脑疾病中的血管损伤方面具有潜力。未来对动物模型的研究可能会推动针对伴有血管损伤的神经系统疾病的新型疗法的开发。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d540/12141489/25fd3d4e3faf/41598_2025_5256_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d540/12141489/9809431fb939/41598_2025_5256_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d540/12141489/c33629413112/41598_2025_5256_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d540/12141489/850fa0a9c7c3/41598_2025_5256_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d540/12141489/57ab62f46f48/41598_2025_5256_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d540/12141489/49c9aefbd47f/41598_2025_5256_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d540/12141489/25fd3d4e3faf/41598_2025_5256_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d540/12141489/9809431fb939/41598_2025_5256_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d540/12141489/c33629413112/41598_2025_5256_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d540/12141489/850fa0a9c7c3/41598_2025_5256_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d540/12141489/57ab62f46f48/41598_2025_5256_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d540/12141489/49c9aefbd47f/41598_2025_5256_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d540/12141489/25fd3d4e3faf/41598_2025_5256_Fig6_HTML.jpg

相似文献

[1]
Development and in vitro characterization of humanized antibodies for blocking human TRPM4 channel.

Sci Rep. 2025-6-5

[2]
Development and characterization of a monoclonal antibody blocking human TRPM4 channel.

Sci Rep. 2021-5-17

[3]
evaluation of monoclonal antibody M4M using a humanised rat model of stroke demonstrates attenuation of reperfusion injury via blocking human TRPM4 channel.

J Drug Target. 2024-4

[4]
TRPM4-specific blocking antibody attenuates reperfusion injury in a rat model of stroke.

Pflugers Arch. 2019-10-29

[5]
Comparison of Anti-oncotic Effect of TRPM4 Blocking Antibody in Neuron, Astrocyte and Vascular Endothelial Cell Under Hypoxia.

Front Cell Dev Biol. 2020-10-19

[6]
Binding epitope for recognition of human TRPM4 channel by monoclonal antibody M4M.

Sci Rep. 2022-11-15

[7]
Non-Invasive Multimodality Imaging Directly Shows TRPM4 Inhibition Ameliorates Stroke Reperfusion Injury.

Transl Stroke Res. 2018-3-22

[8]
Shear stress activates monovalent cation channel transient receptor potential melastatin subfamily 4 in rat atrial myocytes via type 2 inositol 1,4,5-trisphosphate receptors and Ca(2+) release.

J Physiol. 2016-6-1

[9]
Structures of the calcium-activated, non-selective cation channel TRPM4.

Nature. 2017-12-6

[10]
Transient receptor potential melastatin 4 and cell death.

Pflugers Arch. 2012-10-13

本文引用的文献

[1]
Targeting the TRPM4 Channel for Neurologic Diseases: Opportunity and Challenge.

Neuroscientist. 2025-2-26

[2]
Therapeutic antibodies in oncology: an immunopharmacological overview.

Cancer Immunol Immunother. 2024-10-3

[3]
Physiological temperature drives TRPM4 ligand recognition and gating.

Nature. 2024-6

[4]
Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria.

Nat Commun. 2024-3-7

[5]
evaluation of monoclonal antibody M4M using a humanised rat model of stroke demonstrates attenuation of reperfusion injury via blocking human TRPM4 channel.

J Drug Target. 2024-4

[6]
TRPM4 blocking antibody reduces neuronal excitotoxicity by specifically inhibiting glutamate-induced calcium influx under chronic hypoxia.

Neurobiol Dis. 2024-2

[7]
TRPM4 Blocking Antibody Protects Cerebral Vasculature in Delayed Stroke Reperfusion.

Biomedicines. 2023-5-19

[8]
Binding epitope for recognition of human TRPM4 channel by monoclonal antibody M4M.

Sci Rep. 2022-11-15

[9]
Pharmacological Modulation and (Patho)Physiological Roles of TRPM4 Channel-Part 2: TRPM4 in Health and Disease.

Pharmaceuticals (Basel). 2021-12-28

[10]
Development and characterization of a monoclonal antibody blocking human TRPM4 channel.

Sci Rep. 2021-5-17

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