Nanobodies that block gating of the P2X7 ion channel ameliorate inflammation
- PMID: 27881823
- DOI: 10.1126/scitranslmed.aaf8463
Nanobodies that block gating of the P2X7 ion channel ameliorate inflammation
Abstract
Ion channels are desirable therapeutic targets, yet ion channel-directed drugs with high selectivity and few side effects are still needed. Unlike small-molecule inhibitors, antibodies are highly selective for target antigens but mostly fail to antagonize ion channel functions. Nanobodies-small, single-domain antibody fragments-may overcome these problems. P2X7 is a ligand-gated ion channel that, upon sensing adenosine 5'-triphosphate released by damaged cells, initiates a proinflammatory signaling cascade, including release of cytokines, such as interleukin-1β (IL-1β). To further explore its function, we generated and characterized nanobodies against mouse P2X7 that effectively blocked (13A7) or potentiated (14D5) gating of the channel. Systemic injection of nanobody 13A7 in mice blocked P2X7 on T cells and macrophages in vivo and ameliorated experimental glomerulonephritis and allergic contact dermatitis. We also generated nanobody Dano1, which specifically inhibited human P2X7. In endotoxin-treated human blood, Dano1 was 1000 times more potent in preventing IL-1β release than small-molecule P2X7 antagonists currently in clinical development. Our results show that nanobody technology can generate potent, specific therapeutics against ion channels, confirm P2X7 as a therapeutic target for inflammatory disorders, and characterize a potent new drug candidate that targets P2X7.
Copyright © 2016, American Association for the Advancement of Science.
Similar articles
-
Novel biologics targeting the P2X7 ion channel.Curr Opin Pharmacol. 2019 Aug;47:110-118. doi: 10.1016/j.coph.2019.03.001. Epub 2019 Apr 12. Curr Opin Pharmacol. 2019. PMID: 30986625 Review.
-
Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia.Neuropsychopharmacology. 2018 Dec;43(13):2586-2596. doi: 10.1038/s41386-018-0141-6. Epub 2018 Jul 9. Neuropsychopharmacology. 2018. PMID: 30026598 Free PMC article.
-
The evolution of P2X7 antagonists with a focus on CNS indications.Bioorg Med Chem Lett. 2016 Aug 15;26(16):3838-45. doi: 10.1016/j.bmcl.2016.06.048. Epub 2016 Jun 30. Bioorg Med Chem Lett. 2016. PMID: 27426304 Review.
-
Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567.Br J Pharmacol. 2013 Oct;170(3):624-40. doi: 10.1111/bph.12314. Br J Pharmacol. 2013. PMID: 23889535 Free PMC article.
-
Inflammasome activation in bovine monocytes by extracellular ATP does not require the purinergic receptor P2X7.Dev Comp Immunol. 2012 Oct;38(2):312-20. doi: 10.1016/j.dci.2012.06.004. Epub 2012 Jun 19. Dev Comp Immunol. 2012. PMID: 22728096
Cited by
-
Generation of nanobodies from transgenic 'LamaMice' lacking an endogenous immunoglobulin repertoire.Nat Commun. 2024 Jun 3;15(1):4728. doi: 10.1038/s41467-024-48735-x. Nat Commun. 2024. PMID: 38830864 Free PMC article.
-
Generation and characterization of antagonistic anti-human CD39 nanobodies.Front Immunol. 2024 Mar 25;15:1328306. doi: 10.3389/fimmu.2024.1328306. eCollection 2024. Front Immunol. 2024. PMID: 38590528 Free PMC article.
-
Administration of an AAV vector coding for a P2X7-blocking nanobody-based biologic ameliorates colitis in mice.J Nanobiotechnology. 2024 Jan 11;22(1):27. doi: 10.1186/s12951-023-02285-4. J Nanobiotechnology. 2024. PMID: 38212782 Free PMC article.
-
Application of nanotechnology in the treatment of glomerulonephritis: current status and future perspectives.J Nanobiotechnology. 2024 Jan 3;22(1):9. doi: 10.1186/s12951-023-02257-8. J Nanobiotechnology. 2024. PMID: 38169389 Free PMC article. Review.
-
A Species-Specific Anti-Human P2X7 Monoclonal Antibody Reduces Graft-versus-Host Disease in Humanised Mice.Pharmaceutics. 2023 Aug 31;15(9):2263. doi: 10.3390/pharmaceutics15092263. Pharmaceutics. 2023. PMID: 37765233 Free PMC article.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Miscellaneous