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Sci Transl Med. 2016 Nov 23;8(366):366ra162.

Nanobodies that block gating of the P2X7 ion channel ameliorate inflammation.

Author information

1
Institute of Immunology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany.
2
Department of Nephrology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany.
3
Department of Neurology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany.
4
Université de Bordeaux, Institut des Maladies Neurodégénératives, CNRS UMR 5293, Bordeaux 33076, France.
5
Ablynx NV, Technologiepark 21, B-9052 Zwijnaarde, Belgium.
6
Department of Radiology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany.
7
Institute of Immunology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany. nolte@uke.de.

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.

PMID:
27881823
DOI:
10.1126/scitranslmed.aaf8463
[Indexed for MEDLINE]

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